U.S. patent application number 14/254017 was filed with the patent office on 2014-10-23 for methods for treating cancer using dihydropyrazino-pyrazine compound combination therapy.
This patent application is currently assigned to Signal Pharmaceuticals, LLC. The applicant listed for this patent is Signal Pharmaceuticals, LLC. Invention is credited to KRISTEN MAE HEGE, RAMA K. NARLA, HEATHER RAYMON, TOSHIYA TSUJI.
Application Number | 20140315900 14/254017 |
Document ID | / |
Family ID | 50736200 |
Filed Date | 2014-10-23 |
United States Patent
Application |
20140315900 |
Kind Code |
A1 |
RAYMON; HEATHER ; et
al. |
October 23, 2014 |
METHODS FOR TREATING CANCER USING DIHYDROPYRAZINO-PYRAZINE COMPOUND
COMBINATION THERAPY
Abstract
Provided herein are methods for treating or preventing a cancer,
comprising administering an effective amount of a
Dihydropyrazino-Pyrazine Compound and an effective amount of an
androgen receptor antagonist to a patient having a cancer.
Inventors: |
RAYMON; HEATHER; (San Diego,
CA) ; TSUJI; TOSHIYA; (San Diego, CA) ; NARLA;
RAMA K.; (San Diego, CA) ; HEGE; KRISTEN MAE;
(Burlingame, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Signal Pharmaceuticals, LLC |
San Diego |
CA |
US |
|
|
Assignee: |
Signal Pharmaceuticals, LLC
San Diego
CA
|
Family ID: |
50736200 |
Appl. No.: |
14/254017 |
Filed: |
April 16, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61815509 |
Apr 24, 2013 |
|
|
|
61813038 |
Apr 17, 2013 |
|
|
|
Current U.S.
Class: |
514/234.2 ;
514/249 |
Current CPC
Class: |
A61P 35/04 20180101;
A61P 43/00 20180101; A61K 31/506 20130101; A61K 31/4985 20130101;
A61K 31/501 20130101; A61K 45/06 20130101; A61P 13/08 20180101;
A61P 35/00 20180101; A61K 31/5377 20130101; A61K 31/4166 20130101;
A61K 31/4985 20130101; A61K 2300/00 20130101; A61K 31/4166
20130101; A61K 2300/00 20130101 |
Class at
Publication: |
514/234.2 ;
514/249 |
International
Class: |
A61K 31/4985 20060101
A61K031/4985; A61K 31/501 20060101 A61K031/501; A61K 31/5377
20060101 A61K031/5377; A61K 31/4166 20060101 A61K031/4166; A61K
31/506 20060101 A61K031/506 |
Claims
1. A method for treating a cancer, comprising administering an
effective amount of a Dihydropyrazino-Pyrazine Compound in
combination with an effective amount of an androgen receptor
antagonist to a patient having prostate cancer, wherein the
Dihydropyrazino-Pyrazine Compound is a compound of formula (I):
##STR00009## and pharmaceutically acceptable salts, clathrates,
solvates, stereoisomers, tautomers, metabolites, isotopologues and
prodrugs thereof, wherein: R.sup.1 is substituted or unsubstituted
C.sub.1-8 alkyl, substituted or unsubstituted aryl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
heterocyclyl, or substituted or unsubstituted heterocyclylalkyl;
R.sup.2 is H, substituted or unsubstituted C.sub.1-8 alkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted
heterocyclylalkyl, substituted or unsubstituted aralkyl, or
substituted or unsubstituted cycloalkylalkyl; R.sup.3 is H, or a
substituted or unsubstituted C.sub.1-8 alkyl, provided the
Dihydropyrazino-Pyrazine Compound is not
7-(4-hydroxyphenyl)-1-(3-methoxybenzyl)-3,4-dihydropyrazino[2,3-b]pyrazin-
-2(1H)-one.
2. The method of claim 1, wherein the prostate cancer is a relapsed
or refractory prostate cancer.
3. The method of claim 1, wherein the prostate cancer is
castration-resistant prostate cancer.
4. The method of claim 1, wherein the prostate cancer is an
E-twenty six (ETS) overexpressing prostate cancer.
5. The method of claim 1, wherein the prostate cancer is metastatic
castration-resistant prostate cancer.
6. The method of claim 1, wherein the androgen receptor antagonist
is MDV3100.
7. The method of claim 1, wherein the Dihydropyrazino-Pyrazine
Compound is a compound from Table A.
Description
[0001] This application claims the benefit of U.S. Provisional
Application No. 61/813,038, filed Apr. 17, 2013 and U.S.
Provisional Application No. 61/815,509, filed Apr. 24, 2013, the
entire contents of which are incorporated herein by reference.
1. FIELD
[0002] Provided herein are methods for treating or preventing a
cancer, comprising administering an effective amount of a
Dihydropyrazino-Pyrazine Compound and an effective amount of an
androgen receptor antagonist to a patient having a cancer.
2. BACKGROUND
[0003] The connection between abnormal protein phosphorylation and
the cause or consequence of diseases has been known for over 20
years. Accordingly, protein kinases have become a very important
group of drug targets. See Cohen, Nature, 1:309-315 (2002). Various
protein kinase inhibitors have been used clinically in the
treatment of a wide variety of diseases, such as cancer and chronic
inflammatory diseases, including diabetes and stroke. See Cohen,
Eur. J. Biochem., 268:5001-5010 (2001), Protein Kinase Inhibitors
for the Treatment of Disease: The Promise and the Problems,
Handbook of Experimental Pharmacology, Springer Berlin Heidelberg,
167 (2005).
[0004] The protein kinases are a large and diverse family of
enzymes that catalyze protein phosphorylation and play a critical
role in cellular signaling. Protein kinases may exert positive or
negative regulatory effects, depending upon their target protein.
Protein kinases are involved in specific signaling pathways which
regulate cell functions such as, but not limited to, metabolism,
cell cycle progression, cell adhesion, vascular function,
apoptosis, and angiogenesis. Malfunctions of cellular signaling
have been associated with many diseases, the most characterized of
which include cancer and diabetes. The regulation of signal
transduction by cytokines and the association of signal molecules
with protooncogenes and tumor suppressor genes have been well
documented. Similarly, the connection between diabetes and related
conditions, and deregulated levels of protein kinases, has been
demonstrated. See e.g., Sridhar et al. Pharmaceutical Research,
17(11):1345-1353 (2000). Viral infections and the conditions
related thereto have also been associated with the regulation of
protein kinases. Park et al. Cell 101 (7): 777-787 (2000).
[0005] Because protein kinases regulate nearly every cellular
process, including metabolism, cell proliferation, cell
differentiation, and cell survival, they are attractive targets for
therapeutic intervention for various disease states. For example,
cell-cycle control and angiogenesis, in which protein kinases play
a pivotal role are cellular processes associated with numerous
disease conditions such as but not limited to cancer, inflammatory
diseases, abnormal angiogenesis and diseases related thereto,
atherosclerosis, macular degeneration, diabetes, obesity, and
pain.
[0006] Protein kinases have become attractive targets for the
treatment of cancers. Fabbro et al., Pharmacology &
Therapeutics 93:79-98 (2002). It has been proposed that the
involvement of protein kinases in the development of human
malignancies may occur by: (1) genomic rearrangements (e.g.,
BCR-ABL in chronic myelogenous leukemia), (2) mutations leading to
constitutively active kinase activity, such as acute myelogenous
leukemia and gastrointestinal tumors, (3) deregulation of kinase
activity by activation of oncogenes or loss of tumor suppressor
functions, such as in cancers with oncogenic RAS, (4) deregulation
of kinase activity by over-expression, as in the case of EGFR and
(5) ectopic expression of growth factors that can contribute to the
development and maintenance of the neoplastic phenotype. Fabbro et
al., Pharmacology & Therapeutics 93:79-98 (2002).
[0007] The elucidation of the intricacy of protein kinase pathways
and the complexity of the relationship and interaction among and
between the various protein kinases and kinase pathways highlights
the importance of developing pharmaceutical agents capable of
acting as protein kinase modulators, regulators or inhibitors that
have beneficial activity on multiple kinases or multiple kinase
pathways. Accordingly, there remains a need for new kinase
modulators.
[0008] The protein named mTOR (mammalian target of rapamycin),
which is also called FRAP, RAFTI or RAPT1), is a 2549-amino acid
Ser/Thr protein kinase, that has been shown to be one of the most
critical proteins in the mTOR/PI3K/Akt pathway that regulates cell
growth and proliferation. Georgakis and Younes Expert Rev.
Anticancer Ther. 6(1):131-140 (2006). mTOR exists within two
complexes, mTORC1 and mTORC2. While mTORC1 is sensitive to
rapamycin analogs (such as temsirolimus or everolimus), mTORC2 is
largely rapamycin-insensitive. Notably, rapamycin is not a TOR
kinase inhibitor. Several mTOR inhibitors have been or are being
evaluated in clinical trials for the treatment of cancer.
Temsirolimus was approved for use in renal cell carcinoma in 2007
and sirolimus was approved in 1999 for the prophylaxis of renal
transplant rejection. Everolimus was approved in 2009 for renal
cell carcinoma patients that have progressed on vascular
endothelial growth factor receptor inhibitors, in 2010 for
subependymal giant cell astrocytoma (SEGA) associated with tuberous
sclerosis (TS) in patients who require therapy but are not
candidates for surgical resection, and in 2011 for progressive
neuroendocrine tumors of pancreatic origin (PNET) in patients with
unresectable, locally advanced or metastatic disease. There remains
a need for TOR kinase inhibitors that inhibit both mTORC1 and
mTORC2 complexes.
[0009] DNA-dependent protein kinase (DNA-PK) is a serine/threonine
kinase involved in the repair of DNA double strand breaks (DSBs).
DSBs are considered to be the most lethal DNA lesion and occur
endogenously or in response to ionizing radiation and
chemotherapeutics (for review see Jackson, S. P., Bartek, J. The
DNA-damage response in human biology and disease. Nature Rev 2009;
461:1071-1078). If left unrepaired, DSBs will lead to cell cycle
arrest and/or cell death (Hoeijmakers, J. H. J. Genome maintenance
mechanisms for preventing cancer. Nature 2001; 411: 366-374; van
Gent, D. C., Hoeijmakers, J. H., Kanaar, R. Chromosomal stability
and the DNA double-stranded break connection. Nat Rev Genet 2001;
2: 196-206). In response to the insult, cells have developed
complex mechanisms to repair such breaks and these mechanisms may
form the basis of therapeutic resistance. There are two major
pathways used to repair DSBs, non-homologous end joining (NHEJ) and
homologous recombination (HR). NHEJ brings broken ends of the DNA
together and rejoins them without reference to a second template
(Collis, S. J., DeWeese, T. L., Jeggo P. A., Parker, A. R. The life
and death of DNA-PK. Oncogene 2005; 24: 949-961). In contrast, HR
is dependent on the proximity of the sister chromatid which
provides a template to mediate faithful repair (Takata, M., Sasaki,
M. S., Sonoda, E., Morrison, C., Hashimoto, M., Utsumi, H., et al.
Homologous recombination and non-homologous end joining pathways of
DNA double-strand break repair have overlapping roles in the
maintenance of chromosomal integrity in vertebrate cells. EMBO J
1998; 17: 5497-5508; Haber, J. E. Partners and pathways repairing a
double-strand break. Trends Genet 2000; 16: 259-264). NHEJ repairs
the majority of DSBs. In NHEJ, DSBs are recognized by the Ku
protein that binds and then activates the catalytic subunit of
DNA-PK. This leads to recruitment and activation of end-processing
enzymes, polymerases and DNA ligase IV (Collis, S. J., DeWeese, T.
L., Jeggo P. A., Parker, A. R. The life and death of DNA-PK.
Oncogene 2005; 24: 949-961). NHEJ is primarily controlled by DNA-PK
and thus inhibition of DNA-PK is an attractive approach to
modulating the repair response to exogenously induced DSBs. Cells
deficient in components of the NHEJ pathway are defective in DSB
repair and highly sensitive to ionizing radiation and topoisomerase
poisons (reviewed by Smith, G. C. M., Jackson, S. P. The
DNA-dependent protein kinase. Genes Dev 1999; 13: 916-934; Jeggo,
P. A., Caldecott, K., Pidsley, S., Banks, G. R. Sensitivity of
Chinese hamster ovary mutants defective in DNA double strand break
repair to topoisomerase II inhibitors. Cancer Res 1989; 49:
7057-7063). A DNA-PK inhibitor has been reported to have the same
effect of sensitizing cancer cells to therapeutically induced DSBs
(Smith, G. C. M., Jackson, S. P. The DNA-dependent protein kinase.
Genes Dev 1999; 13: 916-934).
[0010] Citation or identification of any reference in Section 2 of
this application is not to be construed as an admission that the
reference is prior art to the present application.
3. SUMMARY
[0011] Provided herein are methods for treating or preventing a
cancer, comprising administering an effective amount of a
Dihydropyrazino-Pyrazine Compound and an effective amount of an
androgen receptor antagonist to a patient having a cancer.
[0012] In certain embodiments, provided herein are methods for
achieving a Response Evaluation Criteria in Solid Tumors (for
example, RECIST 1.1) of complete response, partial response or
stable disease in a patient having a solid tumor, comprising
administering an effective amount of a Dihydropyrazino-Pyrazine
Compound in combination with an androgen receptor antagonist to
said patient. In certain embodiments, provided herein are methods
for achieving a Prostate Cancer Working Group 2 (PCWG2) Criteria of
complete response, partial response or stable disease in a patient
having prostate cancer, comprising administering an effective
amount of a Dihydropyrazino-Pyrazine Compound in combination with
an androgen receptor antagonist to said patient.
[0013] In certain embodiments, provided herein are methods for
increasing survival without tumor progression of a patient having a
cancer, comprising administering an effective amount of a
Dihydropyrazino-Pyrazine Compound in combination with an effective
amount of an androgen receptor antagonist to said patient.
[0014] In certain embodiments, the Dihydropyrazino-Pyrazine
Compound is a compound as described herein. In certain embodiments,
the androgen receptor antagonist is MDV3100.
[0015] The present embodiments can be understood more fully by
reference to the detailed description and examples, which are
intended to exemplify non-limiting embodiments.
4. BRIEF DESCRIPTION OF THE DRAWINGS
[0016] FIG. 1 depicts Compound 2 monotherapy and MDV3100
monotherapy in an ETS-positive prostate cancer xenograft model.
[0017] FIG. 2 depicts Compound 2 monotherapy, MDV3100 monotherapy
and Compound 2+MDV3100 combination therapy in an ETS-positive
prostate cancer xenograft model.
[0018] FIGS. 3A-3E depict Compound 2 and MDV3100 combination
treatment synergy in apoptosis induction. In FIG. 3A Caspase
activity of single treatment with Compound 2 or MDV3100 of the
LNCaP cell line (ETS+, Androgen dependent) is shown. FIGS. 3B, C
and D show 3 experiments measuring the caspase activity of combined
treatment with Compound 2 and MDV3100: Compound 2 treatment alone
(triangles), the expected additive effect of Compound 2 with 30,
10, 3.3 and 1.1 .mu.M MDV3100 (+), and the actual combination
effect of Compound 2 and MDV3100 treatment (circles), as measured
by caspase induction. FIG. 3E shows an experiment measuring the
caspase activity of treatment with Compound 2 and MDV3100 of the
VCaP cell line (ETS+, Androgen dependent): Compound 2 treatment
alone (triangles), the expected additive effect of Compound 2 with
30, 10, 3.3 and 1.1 .mu.M MDV3100 (+), and the actual combination
effect of Compound 2 and MDV3100 treatment (circles), as measured
by caspase induction.
[0019] FIG. 4 depicts Compound 2 monotherapy, MDV3100 monotherapy
and Compound 2+MDV3100 combination therapy in a LNCap-HR prostate
cancer xenograft model.
5. DETAILED DESCRIPTION
5.1 Definitions
[0020] An "alkyl" group is a saturated, partially saturated, or
unsaturated straight chain or branched non-cyclic hydrocarbon
having from 1 to 10 carbon atoms, typically from 1 to 8 carbons or,
in some embodiments, from 1 to 6, 1 to 4, or 2 to 6 or carbon
atoms. Representative alkyl groups include -methyl, -ethyl,
-n-propyl, -n-butyl, -n-pentyl and -n-hexyl; while saturated
branched alkyls include -isopropyl, -sec-butyl, -isobutyl,
-tert-butyl, -isopentyl, 2-methylpentyl, 3-methylpentyl,
4-methylpentyl, 2,3-dimethylbutyl and the like. Examples of
unsaturated alkyl groups include, but are not limited to, vinyl,
allyl, --CH.dbd.CH(CH.sub.3), --CH.dbd.C(CH.sub.3).sub.2,
--C(CH.sub.3).dbd.CH.sub.2, --C(CH.sub.3).dbd.CH(CH.sub.3),
--C(CH.sub.2CH.sub.3).dbd.CH.sub.2, --C.ident.CH,
--C.ident.C(CH.sub.3), --C.ident.C(CH.sub.2CH.sub.3),
--CH.sub.2C.ident.CH, --CH.sub.2C.ident.C(CH.sub.3) and
--CH.sub.2C.ident.C(CH.sub.2CH.sub.3), among others. An alkyl group
can be substituted or unsubstituted. In certain embodiments, when
the alkyl groups described herein are said to be "substituted,"
they may be substituted with any substituent or substituents as
those found in the exemplary compounds and embodiments disclosed
herein, as well as halogen (chloro, iodo, bromo, or fluoro);
hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro;
cyano; thiol; thioether; imine; imide; amidine; guanidine; enamine;
aminocarbonyl; acylamino; phosphonato; phosphine; thiocarbonyl;
sulfonyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea;
urethane; oxime; hydroxylamine; alkoxyamine; aralkoxyamine;
N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate;
isothiocyanate; cyanate; thiocyanate; B(OH).sub.2, or
O(alkyl)aminocarbonyl.
[0021] An "alkenyl" group is a straight chain or branched
non-cyclic hydrocarbon having from 2 to 10 carbon atoms, typically
from 2 to 8 carbon atoms, and including at least one carbon-carbon
double bond. Representative straight chain and branched
(C.sub.2-C.sub.8)alkenyls include -vinyl, -allyl, -1-butenyl,
-2-butenyl, -isobutylenyl, -1-pentenyl, -2-pentenyl,
-3-methyl-1-butenyl, -2-methyl-2-butenyl, -2,3-dimethyl-2-butenyl,
-1-hexenyl, -2-hexenyl, -3-hexenyl, -1-heptenyl, -2-heptenyl,
-3-heptenyl, -1-octenyl, -2-octenyl, -3-octenyl and the like. The
double bond of an alkenyl group can be unconjugated or conjugated
to another unsaturated group. An alkenyl group can be unsubstituted
or substituted.
[0022] A "cycloalkyl" group is a saturated, or partially saturated
cyclic alkyl group of from 3 to 10 carbon atoms having a single
cyclic ring or multiple condensed or bridged rings which can be
optionally substituted with from 1 to 3 alkyl groups. In some
embodiments, the cycloalkyl group has 3 to 8 ring members, whereas
in other embodiments the number of ring carbon atoms ranges from 3
to 5, 3 to 6, or 3 to 7. Such cycloalkyl groups include, by way of
example, single ring structures such as cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,
1-methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl, and
the like, or multiple or bridged ring structures such as adamantyl
and the like. Examples of unsaturated cycloalkyl groups include
cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl,
pentadienyl, hexadienyl, among others. A cycloalkyl group can be
substituted or unsubstituted. Such substituted cycloalkyl groups
include, by way of example, cyclohexanone and the like.
[0023] An "aryl" group is an aromatic carbocyclic group of from 6
to 14 carbon atoms having a single ring (e.g., phenyl) or multiple
condensed rings (e.g., naphthyl or anthryl). In some embodiments,
aryl groups contain 6-14 carbons, and in others from 6 to 12 or
even 6 to 10 carbon atoms in the ring portions of the groups.
Particular aryls include phenyl, biphenyl, naphthyl and the like.
An aryl group can be substituted or unsubstituted. The phrase "aryl
groups" also includes groups containing fused rings, such as fused
aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl,
and the like).
[0024] A "heteroaryl" group is an aryl ring system having one to
four heteroatoms as ring atoms in a heteroaromatic ring system,
wherein the remainder of the atoms are carbon atoms. In some
embodiments, heteroaryl groups contain 5 to 6 ring atoms, and in
others from 6 to 9 or even 6 to 10 atoms in the ring portions of
the groups. Suitable heteroatoms include oxygen, sulfur and
nitrogen. In certain embodiments, the heteroaryl ring system is
monocyclic or bicyclic. Non-limiting examples include but are not
limited to, groups such as pyrrolyl, pyrazolyl, imidazolyl,
triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyrolyl,
pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl,
benzothiophenyl, furanyl, benzofuranyl (for example,
isobenzofuran-1,3-diimine), indolyl, azaindolyl (for example,
pyrrolopyridyl or 1H-pyrrolo[2,3-b]pyridyl), indazolyl,
benzimidazolyl (for example, 1H-benzo[d]imidazolyl), imidazopyridyl
(for example, azabenzimidazolyl, 3H-imidazo[4,5-b]pyridyl or
1H-imidazo[4,5-b]pyridyl), pyrazolopyridyl, triazolopyridyl,
benzotriazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl,
isoxazolopyridyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl,
guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl,
quinoxalinyl, and quinazolinyl groups.
[0025] A "heterocyclyl" is an aromatic (also referred to as
heteroaryl) or non-aromatic cycloalkyl in which one to four of the
ring carbon atoms are independently replaced with a heteroatom from
the group consisting of O, S and N. In some embodiments,
heterocyclyl groups include 3 to 10 ring members, whereas other
such groups have 3 to 5, 3 to 6, or 3 to 8 ring members.
Heterocyclyls can also be bonded to other groups at any ring atom
(i.e., at any carbon atom or heteroatom of the heterocyclic ring).
A heterocyclylalkyl group can be substituted or unsubstituted.
Heterocyclyl groups encompass unsaturated, partially saturated and
saturated ring systems, such as, for example, imidazolyl,
imidazolinyl and imidazolidinyl groups. The phrase heterocyclyl
includes fused ring species, including those comprising fused
aromatic and non-aromatic groups, such as, for example,
benzotriazolyl, 2,3-dihydrobenzo[1,4]dioxinyl, and
benzo[1,3]dioxolyl. The phrase also includes bridged polycyclic
ring systems containing a heteroatom such as, but not limited to,
quinuclidyl. Representative examples of a heterocyclyl group
include, but are not limited to, aziridinyl, azetidinyl,
pyrrolidyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl,
tetrahydrothiophenyl, tetrahydrofuranyl, dioxolyl, furanyl,
thiophenyl, pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl,
pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, oxazolyl,
isoxazolyl, thiazolyl, thiazolinyl, isothiazolyl, thiadiazolyl,
oxadiazolyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl,
tetrahydropyranyl (for example, tetrahydro-2H-pyranyl),
tetrahydrothiopyranyl, oxathiane, dioxyl, dithianyl, pyranyl,
pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl,
dihydropyridyl, dihydrodithiinyl, dihydrodithionyl,
homopiperazinyl, quinuclidyl, indolyl, indolinyl, isoindolyl,
azaindolyl(pyrrolopyridyl), indazolyl, indolizinyl, benzotriazolyl,
benzimidazolyl, benzofuranyl, benzothiophenyl, benzthiazolyl,
benzoxadiazolyl, benzoxazinyl, benzodithiinyl, benzoxathiinyl,
benzothiazinyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl,
benzo[1,3]dioxolyl, pyrazolopyridyl,
imidazopyridyl(azabenzimidazolyl; for example,
1H-imidazo[4,5-b]pyridyl, or 1H-imidazo[4,5-b]pyridin-2(3H)-onyl),
triazolopyridyl, isoxazolopyridyl, purinyl, xanthinyl, adeninyl,
guaninyl, quinolinyl, isoquinolinyl, quinolizinyl, quinoxalinyl,
quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, pteridinyl,
thianaphthalenyl, dihydrobenzothiazinyl, dihydrobenzofuranyl,
dihydroindolyl, dihydrobenzodioxinyl, tetrahydroindolyl,
tetrahydroindazolyl, tetrahydrobenzimidazolyl,
tetrahydrobenzotriazolyl, tetrahydropyrrolopyridyl,
tetrahydropyrazolopyridyl, tetrahydroimidazopyridyl,
tetrahydrotriazolopyridyl, and tetrahydroquinolinyl groups.
Representative substituted heterocyclyl groups may be
mono-substituted or substituted more than once, such as, but not
limited to, pyridyl or morpholinyl groups, which are 2-, 3-, 4-,
5-, or 6-substituted, or disubstituted with various substituents
such as those listed below.
[0026] A "cycloalkylalkyl" group is a radical of the formula:
-alkyl-cycloalkyl, wherein alkyl and cycloalkyl are defined above.
Substituted cycloalkylalkyl groups may be substituted at the alkyl,
the cycloalkyl, or both the alkyl and the cycloalkyl portions of
the group. Representative cycloalkylalkyl groups include but are
not limited to cyclopentylmethyl, cyclopentylethyl,
cyclohexylmethyl, cyclohexylethyl, and cyclohexylpropyl.
Representative substituted cycloalkylalkyl groups may be
mono-substituted or substituted more than once.
[0027] An "aralkyl" group is a radical of the formula: -alkyl-aryl,
wherein alkyl and aryl are defined above. Substituted aralkyl
groups may be substituted at the alkyl, the aryl, or both the alkyl
and the aryl portions of the group. Representative aralkyl groups
include but are not limited to benzyl and phenethyl groups and
fused (cycloalkylaryl)alkyl groups such as 4-ethyl-indanyl.
[0028] A "heterocyclylalkyl" group is a radical of the formula:
-alkyl-heterocyclyl, wherein alkyl and heterocyclyl are defined
above. Substituted heterocyclylalkyl groups may be substituted at
the alkyl, the heterocyclyl, or both the alkyl and the heterocyclyl
portions of the group. Representative heterocylylalkyl groups
include but are not limited to 4-ethyl-morpholinyl,
4-propylmorpholinyl, furan-2-yl methyl, furan-3-yl methyl,
pyrdine-3-yl methyl, (tetrahydro-2H-pyran-4-yl)methyl,
(tetrahydro-2H-pyran-4-yl)ethyl, tetrahydrofuran-2-yl methyl,
tetrahydrofuran-2-yl ethyl, and indol-2-yl propyl.
[0029] A "halogen" is chloro, iodo, bromo, or fluoro.
[0030] A "hydroxyalkyl" group is an alkyl group as described above
substituted with one or more hydroxy groups.
[0031] An "alkoxy" group is --O-(alkyl), wherein alkyl is defined
above.
[0032] An "alkoxyalkyl" group is -(alkyl)-O-(alkyl), wherein alkyl
is defined above.
[0033] An "amine" group is a radical of the formula:
--NH.sub.2.
[0034] A "hydroxylamine" group is a radical of the formula:
--N(R.sup.#)OH or --NHOH, wherein R.sup.# is a substituted or
unsubstituted alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,
heterocyclyl or heterocyclylalkyl group as defined herein.
[0035] An "alkoxyamine" group is a radical of the formula:
--N(R.sup.#)O-alkyl or --NHO-alkyl, wherein R.sup.# is as defined
above.
[0036] An "aralkoxyamine" group is a radical of the formula:
--N(R.sup.#)O-aryl or --NHO-aryl, wherein R.sup.# is as defined
above.
[0037] An "alkylamine" group is a radical of the formula:
--NH-alkyl or --N(alkyl).sub.2, wherein each alkyl is independently
as defined above.
[0038] An "aminocarbonyl" group is a radical of the formula:
--C(.dbd.O)N(R.sup.#).sub.2, --C(.dbd.O)NH(R.sup.#) or
--C(.dbd.O)NH.sub.2, wherein each R.sup.# is as defined above.
[0039] An "acylamino" group is a radical of the formula:
--NHC(.dbd.O)(R.sup.#) or --N(alkyl)C(.dbd.O)(R.sup.#), wherein
each alkyl and R.sup.# are independently as defined above.
[0040] An "O(alkyl)aminocarbonyl" group is a radical of the
formula: --O(alkyl)C(.dbd.O)N(R.sup.#).sub.2,
--O(alkyl)C(.dbd.O)NH(R.sup.#) or --O(alkyl)C(.dbd.O)NH.sub.2,
wherein each R.sup.# is independently as defined above.
[0041] An "N-oxide" group is a radical of the formula:
--N.sup.+--O.sup.-.
[0042] A "carboxy" group is a radical of the formula:
--C(.dbd.O)OH.
[0043] A "ketone" group is a radical of the formula:
--C(.dbd.O)(R.sup.#), wherein R.sup.# is as defined above.
[0044] An "aldehyde" group is a radical of the formula:
--CH(.dbd.O).
[0045] An "ester" group is a radical of the formula:
--C(.dbd.O)O(R.sup.#) or --OC(.dbd.O)(R.sup.#), wherein R.sup.# is
as defined above.
[0046] A "urea" group is a radical of the formula:
--N(alkyl)C(.dbd.O)N(R.sup.#).sub.2,
--N(alkyl)C(.dbd.O)NH(R.sup.#), --N(alkyl)C(.dbd.O)NH.sub.2,
--NHC(.dbd.O)N(R.sup.#).sub.2, --NHC(.dbd.O)NH(R.sup.#), or
--NHC(.dbd.O)NH.sub.2.sup.#, wherein each alkyl and R.sup.# are
independently as defined above.
[0047] An "imine" group is a radical of the formula:
--N.dbd.C(R.sup.#).sub.2 or --C(R.sup.#).dbd.N(R.sup.#), wherein
each R.sup.# is independently as defined above.
[0048] An "imide" group is a radical of the formula:
--C(.dbd.O)N(R.sup.#)C(.dbd.O)(R.sup.#) or
--N((C.dbd.O)(R.sup.#)).sub.2, wherein each R.sup.# is
independently as defined above.
[0049] A "urethane" group is a radical of the formula:
--OC(.dbd.O)N(R.sup.#).sub.2, --OC(.dbd.O)NH(R.sup.#),
--N(R.sup.#)C(.dbd.O)O(R.sup.#), or --NHC(.dbd.O)O(R.sup.#),
wherein each R.sup.# is independently as defined above.
[0050] An "amidine" group is a radical of the formula:
--C(.dbd.N(R.sup.#))N(R.sup.#).sub.2,
--C(.dbd.N(R.sup.#))NH(R.sup.#), --C(.dbd.N(R.sup.#))NH.sub.2,
--C(.dbd.NH)N(R.sup.#).sub.2, --C(.dbd.NH)NH(R.sup.#),
--C(.dbd.NH)NH.sub.2, --N.dbd.C(R.sup.#)N(R.sup.#).sub.2,
--N.dbd.C(R.sup.#)NH(R.sup.#), --N.dbd.C(R.sup.#)NH.sub.2,
--N(R.sup.#)C(R.sup.#).dbd.N(R.sup.#),
--NHC(R.sup.#).dbd.N(R.sup.#), --N(R.sup.#)C(R.sup.#).dbd.NH, or
--NHC(R.sup.#).dbd.NH, wherein each R.sup.# is independently as
defined above.
[0051] A "guanidine" group is a radical of the formula:
--N(R.sup.#)C(.dbd.N(R.sup.#))N(R.sup.#).sub.2,
--NHC(.dbd.N(R.sup.#))N(R.sup.#).sub.2,
--N(R.sup.#)C(.dbd.NH)N(R.sup.#).sub.2,
--N(R.sup.#)C(.dbd.N(R.sup.#))NH(R.sup.#),
--N(R.sup.#)C(.dbd.N(R.sup.#))NH.sub.2,
--NHC(.dbd.NH)N(R.sup.#).sub.2, --NHC(.dbd.N(R.sup.#))NH(R.sup.#),
--NHC(.dbd.N(R.sup.#))NH.sub.2, --NHC(.dbd.NH)NH(R.sup.#),
--NHC(.dbd.NH)NH.sub.2, --N.dbd.C(N(R.sup.#).sub.2).sub.2,
--N.dbd.C(NH(R.sup.#)).sub.2, or --N.dbd.C(NH.sub.2).sub.2, wherein
each R.sup.# is independently as defined above.
[0052] A "enamine" group is a radical of the formula:
--N(R.sup.#)C(R.sup.#).dbd.C(R.sup.#).sub.2,
--NHC(R.sup.#).dbd.C(R.sup.#).sub.2,
--C(N(R.sup.#).sub.2).dbd.C(R.sup.#).sub.2,
--C(NH(R.sup.#)).dbd.C(R.sup.#).sub.2,
--C(NH.sub.2).dbd.C(R.sup.#).sub.2,
--C(R.sup.#).dbd.C(R.sup.#)(N(R.sup.#).sub.2),
--C(R.sup.#).dbd.C(R.sup.#)(NH(R.sup.#)) or
--C(R.sup.#).dbd.C(R.sup.#)(NH.sub.2), wherein each R.sup.# is
independently as defined above.
[0053] An "oxime" group is a radical of the formula:
--C(.dbd.NO(R.sup.#))(R.sup.#), --C(.dbd.NOH)(R.sup.#),
--CH(.dbd.NO(R.sup.#)), or --CH(.dbd.NOH), wherein each R.sup.# is
independently as defined above.
[0054] A "hydrazide" group is a radical of the formula:
--C(.dbd.O)N(R.sup.#)N(R.sup.#).sub.2,
--C(.dbd.O)NHN(R.sup.#).sub.2, --C(.dbd.O)N(R.sup.#)NH(R.sup.#),
--C(.dbd.O)N(R.sup.#)NH.sub.2, --C(.dbd.O)NHNH(R.sup.#).sub.2, or
--C(.dbd.O)NHNH.sub.2, wherein each R.sup.# is independently as
defined above.
[0055] A "hydrazine" group is a radical of the formula:
--N(R.sup.#)N(R.sup.#).sub.2, --NHN(R.sup.#).sub.2,
--N(R.sup.#)NH(R.sup.#), --N(R.sup.#)NH.sub.2,
--NHNH(R.sup.#).sub.2, or --NHNH.sub.2, wherein each R.sup.# is
independently as defined above.
[0056] A "hydrazone" group is a radical of the formula:
--C(.dbd.N--N(R.sup.#).sub.2)(R.sup.#).sub.2,
--C(.dbd.N--NH(R.sup.#))(R.sup.#).sub.2,
--C(.dbd.N--NH.sub.2)(R.sup.#).sub.2,
--N(R.sup.#)(N.dbd.C(R.sup.#).sub.2), or
--NH(N.dbd.C(R.sup.#).sub.2), wherein each R.sup.# is independently
as defined above.
[0057] An "azide" group is a radical of the formula: --N.sub.3.
[0058] An "isocyanate" group is a radical of the formula:
--N.dbd.C.dbd.O.
[0059] An "isothiocyanate" group is a radical of the formula:
--N.dbd.C.dbd.S.
[0060] A "cyanate" group is a radical of the formula: --OCN.
[0061] A "thiocyanate" group is a radical of the formula:
--SCN.
[0062] A "thioether" group is a radical of the formula;
--S(R.sup.#), wherein R.sup.# is as defined above.
[0063] A "thiocarbonyl" group is a radical of the formula:
--C(.dbd.S)(R.sup.#), wherein R.sup.# is as defined above.
[0064] A "sulfinyl" group is a radical of the formula:
--S(.dbd.O)(R.sup.#), wherein R.sup.# is as defined above.
[0065] A "sulfone" group is a radical of the formula:
--S(.dbd.O).sub.2(R.sup.#), wherein R.sup.# is as defined
above.
[0066] A "sulfonylamino" group is a radical of the formula:
--NHSO.sub.2(R.sup.#) or --N(alkyl)SO.sub.2(R.sup.#), wherein each
alkyl and R.sup.# are defined above.
[0067] A "sulfonamide" group is a radical of the formula:
--S(.dbd.O).sub.2N(R.sup.#).sub.2, or --S(.dbd.O).sub.2NH(R.sup.#),
or --S(.dbd.O).sub.2NH.sub.2, wherein each R.sup.# is independently
as defined above.
[0068] A "phosphonate" group is a radical of the formula:
--P(.dbd.O)(O(R.sup.#)).sub.2, --P(.dbd.O)(OH).sub.2,
--OP(.dbd.O)(O(R.sup.#)(R.sup.#), or --OP(.dbd.O)(OH)(R.sup.#),
wherein each R.sup.# is independently as defined above.
[0069] A "phosphine" group is a radical of the formula:
--P(R.sup.#).sub.2, wherein each R.sup.# is independently as
defined above.
[0070] When the groups described herein, with the exception of
alkyl group are said to be "substituted," they may be substituted
with any appropriate substituent or substituents. Illustrative
examples of substituents are those found in the exemplary compounds
and embodiments disclosed herein, as well as halogen (chloro, iodo,
bromo, or fluoro); alkyl; hydroxyl; alkoxy; alkoxyalkyl; amino;
alkylamino; carboxy; nitro; cyano; thiol; thioether; imine; imide;
amidine; guanidine; enamine; aminocarbonyl; acylamino; phosphonate;
phosphine; thiocarbonyl; sulfinyl; sulfone; sulfonamide; ketone;
aldehyde; ester; urea; urethane; oxime; hydroxylamine; alkoxyamine;
aralkoxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide;
isocyanate; isothiocyanate; cyanate; thiocyanate; oxygen (.dbd.O);
B(OH).sub.2, O(alkyl)aminocarbonyl; cycloalkyl, which may be
monocyclic or fused or non-fused polycyclic (e.g., cyclopropyl,
cyclobutyl, cyclopentyl, or cyclohexyl), or a heterocyclyl, which
may be monocyclic or fused or non-fused polycyclic (e.g.,
pyrrolidyl, piperidyl, piperazinyl, morpholinyl, or thiazinyl);
monocyclic or fused or non-fused polycyclic aryl or heteroaryl
(e.g., phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl,
imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl,
pyrazolyl, pyridinyl, quinolinyl, isoquinolinyl, acridinyl,
pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl,
benzothiophenyl, or benzofuranyl) aryloxy; aralkyloxy;
heterocyclyloxy; and heterocyclyl alkoxy.
[0071] As used herein, the term "pharmaceutically acceptable
salt(s)" refers to a salt prepared from a pharmaceutically
acceptable non-toxic acid or base including an inorganic acid and
base and an organic acid and base. Suitable pharmaceutically
acceptable base addition salts of the Dihydropyrazino-Pyrazine
Compounds include, but are not limited to metallic salts made from
aluminum, calcium, lithium, magnesium, potassium, sodium and zinc
or organic salts made from lysine, N,N'-dibenzylethylenediamine,
chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine
(N-methylglucamine) and procaine. Suitable non-toxic acids include,
but are not limited to, inorganic and organic acids such as acetic,
alginic, anthranilic, benzenesulfonic, benzoic, camphorsulfonic,
citric, ethenesulfonic, formic, fumaric, furoic, galacturonic,
gluconic, glucuronic, glutamic, glycolic, hydrobromic,
hydrochloric, isethionic, lactic, maleic, malic, mandelic,
methanesulfonic, mucic, nitric, pamoic, pantothenic, phenylacetic,
phosphoric, propionic, salicylic, stearic, succinic, sulfanilic,
sulfuric, tartaric acid, and p-toluenesulfonic acid. Specific
non-toxic acids include hydrochloric, hydrobromic, phosphoric,
sulfuric, and methanesulfonic acids. Examples of specific salts
thus include hydrochloride and mesylate salts. Others are
well-known in the art, see for example, Remington's Pharmaceutical
Sciences, 18.sup.th eds., Mack Publishing, Easton Pa. (1990) or
Remington: The Science and Practice of Pharmacy, 19.sup.th eds.,
Mack Publishing, Easton Pa. (1995).
[0072] As used herein and unless otherwise indicated, the term
"clathrate" means a Dihydropyrazino-Pyrazine Compound, or a salt
thereof, in the form of a crystal lattice that contains spaces
(e.g., channels) that have a guest molecule (e.g., a solvent or
water) trapped within or a crystal lattice wherein a
Dihydropyrazino-Pyrazine Compound is a guest molecule.
[0073] As used herein and unless otherwise indicated, the term
"solvate" means a Dihydropyrazino-Pyrazine Compound, or a salt
thereof, that further includes a stoichiometric or
non-stoichiometric amount of a solvent bound by non-covalent
intermolecular forces. In one embodiment, the solvate is a
hydrate.
[0074] As used herein and unless otherwise indicated, the term
"hydrate" means a Dihydropyrazino-Pyrazine Compound, or a salt
thereof, that further includes a stoichiometric or
non-stoichiometric amount of water bound by non-covalent
intermolecular forces.
[0075] As used herein and unless otherwise indicated, the term
"prodrug" means a Dihydropyrazino-Pyrazine Compound derivative that
can hydrolyze, oxidize, or otherwise react under biological
conditions (in vitro or in vivo) to provide an active compound,
particularly a Dihydropyrazino-Pyrazine Compound. Examples of
prodrugs include, but are not limited to, derivatives and
metabolites of a Dihydropyrazino-Pyrazine Compound that include
biohydrolyzable moieties such as biohydrolyzable amides,
biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable
carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate
analogues. In certain embodiments, prodrugs of compounds with
carboxyl functional groups are the lower alkyl esters of the
carboxylic acid. The carboxylate esters are conveniently formed by
esterifying any of the carboxylic acid moieties present on the
molecule. Prodrugs can typically be prepared using well-known
methods, such as those described by Burger's Medicinal Chemistry
and Drug Discovery 6.sup.th ed. (Donald J. Abraham ed., 2001,
Wiley) and Design and Application of Prodrugs (H. Bundgaard ed.,
1985, Harwood Academic Publishers Gmfh).
[0076] As used herein and unless otherwise indicated, the term
"stereoisomer" or "stereomerically pure" means one stereoisomer of
a Dihydropyrazino-Pyrazine Compound that is substantially free of
other stereoisomers of that compound. For example, a
stereomerically pure compound having one chiral center will be
substantially free of the opposite enantiomer of the compound. A
stereomerically pure compound having two chiral centers will be
substantially free of other diastereomers of the compound. A
typical stereomerically pure compound comprises greater than about
80% by weight of one stereoisomer of the compound and less than
about 20% by weight of other stereoisomers of the compound, greater
than about 90% by weight of one stereoisomer of the compound and
less than about 10% by weight of the other stereoisomers of the
compound, greater than about 95% by weight of one stereoisomer of
the compound and less than about 5% by weight of the other
stereoisomers of the compound, or greater than about 97% by weight
of one stereoisomer of the compound and less than about 3% by
weight of the other stereoisomers of the compound. The
Dihydropyrazino-Pyrazine Compounds can have chiral centers and can
occur as racemates, individual enantiomers or diastereomers, and
mixtures thereof. All such isomeric forms are included within the
embodiments disclosed herein, including mixtures thereof. The use
of stereomerically pure forms of such Dihydropyrazino-Pyrazine
Compounds, as well as the use of mixtures of those forms are
encompassed by the embodiments disclosed herein. For example,
mixtures comprising equal or unequal amounts of the enantiomers of
a particular Dihydropyrazino-Pyrazine Compound may be used in
methods and compositions disclosed herein. These isomers may be
asymmetrically synthesized or resolved using standard techniques
such as chiral columns or chiral resolving agents. See, e.g.,
Jacques, J., et al., Enantiomers, Racemates and Resolutions
(Wiley-Interscience, New York, 1981); Wilen, S. H., et al.,
Tetrahedron 33:2725 (1977); Eliel, E. L., Stereochemistry of Carbon
Compounds (McGraw-Hill, NY, 1962); and Wilen, S. H., Tables of
Resolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed.,
Univ. of Notre Dame Press, Notre Dame, 1N, 1972).
[0077] It should also be noted the Dihydropyrazino-Pyrazine
Compounds can include E and Z isomers, or a mixture thereof, and
cis and trans isomers or a mixture thereof. In certain embodiments,
the Dihydropyrazino-Pyrazine Compounds are isolated as either the
cis or trans isomer. In other embodiments, the
Dihydropyrazino-Pyrazine Compounds are a mixture of the cis and
trans isomers.
[0078] "Tautomers" refers to isomeric forms of a compound that are
in equilibrium with each other. The concentrations of the isomeric
forms will depend on the environment the compound is found in and
may be different depending upon, for example, whether the compound
is a solid or is in an organic or aqueous solution. For example, in
aqueous solution, pyrazoles may exhibit the following isomeric
forms, which are referred to as tautomers of each other:
##STR00001##
[0079] As readily understood by one skilled in the art, a wide
variety of functional groups and other structures may exhibit
tautomerism and all tautomers of the Dihydropyrazino-Pyrazine
Compounds are within the scope of the present invention.
[0080] It should also be noted the Dihydropyrazino-Pyrazine
Compounds can contain unnatural proportions of atomic isotopes at
one or more of the atoms. For example, the compounds may be
radiolabeled with radioactive isotopes, such as for example tritium
(.sup.3H), iodine-125 (.sup.125I), sulfur-35 (.sup.35S), or
carbon-14 (.sup.14C), or may be isotopically enriched, such as with
deuterium (.sup.2H), carbon-13 (.sup.13C), or nitrogen-15
(.sup.15N). As used herein, an "isotopologue" is an isotopically
enriched compound. The term "isotopically enriched" refers to an
atom having an isotopic composition other than the natural isotopic
composition of that atom. "Isotopically enriched" may also refer to
a compound containing at least one atom having an isotopic
composition other than the natural isotopic composition of that
atom. The term "isotopic composition" refers to the amount of each
isotope present for a given atom. Radiolabeled and isotopically
enriched compounds are useful as therapeutic agents, e.g., cancer
and inflammation therapeutic agents, research reagents, e.g.,
binding assay reagents, and diagnostic agents, e.g., in vivo
imaging agents. All isotopic variations of the
Dihydropyrazino-Pyrazine Compounds as described herein, whether
radioactive or not, are intended to be encompassed within the scope
of the embodiments provided herein. In some embodiments, there are
provided isotopologues of the Dihydropyrazino-Pyrazine Compounds,
for example, the isotopologues are deuterium, carbon-13, or
nitrogen-15 enriched Dihydropyrazino-Pyrazine Compounds.
[0081] It should be noted that if there is a discrepancy between a
depicted structure and a name for that structure, the depicted
structure is to be accorded more weight.
[0082] "Treating" as used herein, means an alleviation, in whole or
in part, of a cancer or a symptom associated with a cancer, or
slowing, or halting of further progression or worsening of those
symptoms.
[0083] "Preventing" as used herein, means the prevention of the
onset, recurrence or spread, in whole or in part, of a cancer, or a
symptom thereof.
[0084] The term "effective amount" in connection with an
Dihydropyrazino-Pyrazine Compound or an androgen receptor
antagonist means an amount alone or in combination capable of
alleviating, in whole or in part, a symptom associated with a
cancer, or slowing or halting further progression or worsening of
those symptoms, or treating or preventing a cancer in a subject
having or at risk for having a cancer. The effective amount of the
Dihydropyrazino-Pyrazine Compound or an androgen receptor
antagonist, for example in a pharmaceutical composition, may be at
a level that will exercise the desired effect; for example, about
0.005 mg/kg of a subject's body weight to about 100 mg/kg of a
patient's body weight in unit dosage for both oral and parenteral
administration.
[0085] The term "cancer" refers to any of various malignant
neoplasms characterized by the proliferation of cells that can
invade surrounding tissue and metastasize to new body sites. Both
benign and malignant tumors are classified according to the type of
tissue in which they are found. For example, fibromas are neoplasms
of fibrous connective tissue, and melanomas are abnormal growths of
pigment (melanin) cells. Malignant tumors originating from
epithelial tissue, e.g., in skin, bronchi, and stomach, are termed
carcinomas. Malignancies of epithelial glandular tissue such as are
found in the breast, prostate, and colon, are known as
adenocarcinomas. Malignant growths of connective tissue, e.g.,
muscle, cartilage, lymph tissue, and bone, are called sarcomas.
Lymphomas and leukemias are malignancies arising among white blood
cells. Through the process of metastasis, tumor cell migration to
other areas of the body establishes neoplasms in areas away from
the site of initial appearance. Bone tissues are one of the most
favored sites of metastases of malignant tumors, occurring in about
30% of all cancer cases. Among malignant tumors, cancers of the
lung, breast, prostate or the like are particularly known to be
likely to metastasize to bone.
[0086] In the context of neoplasm, cancer, tumor growth or tumor
cell growth, inhibition may be assessed by delayed appearance of
primary or secondary tumors, slowed development of primary or
secondary tumors, decreased occurrence of primary or secondary
tumors, slowed or decreased severity of secondary effects of
disease, arrested tumor growth and regression of tumors, among
others. In the extreme, complete inhibition, is referred to herein
as prevention or chemoprevention. In this context, the term
"prevention" includes either preventing the onset of clinically
evident neoplasia altogether or preventing the onset of a
preclinically evident stage of neoplasia in individuals at risk.
Also intended to be encompassed by this definition is the
prevention of transformation into malignant cells or to arrest or
reverse the progression of premalignant cells to malignant cells.
This includes prophylactic treatment of those at risk of developing
the neoplasia.
[0087] As used herein, and unless otherwise specified, the term "in
combination with" includes the administration of two or more
therapeutic agents simultaneously, concurrently, or sequentially
within no specific time limits unless otherwise indicated. In one
embodiment, a Dihydropyrazino-Pyrazine Compound is administered in
combination with an androgen receptor antagonist. In one
embodiment, the agents are present in the cell or in the subject's
body at the same time or exert their biological or therapeutic
effect at the same time. In one embodiment, the therapeutic agents
are in the same composition or unit dosage form. In other
embodiments, the therapeutic agents are in separate compositions or
unit dosage forms. In certain embodiments, a first agent can be
administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45
minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48
hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5
weeks, 6 weeks, 8 weeks, or 12 weeks before), essentially
concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes,
30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12
hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3
weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the
administration of a second therapeutic agent, or any combination
thereof. For example, in one embodiment, the first agent can be
administered prior to the second therapeutic agent, for e.g. 1
week. In another, the first agent can be administered prior to (for
example 1 day prior) and then concomitant with the second
therapeutic agent.
[0088] The terms "patient" and "subject" as used herein include an
animal, including, but not limited to, an animal such as a cow,
monkey, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse,
rat, rabbit or guinea pig, in one embodiment a mammal, in another
embodiment a human. In one embodiment, a "patient" or "subject" is
a human having a cancer. In one embodiment, the patient" or
"subject" is a human having metastatic castration-resistant
prostate cancer who has previously received docetaxel.
[0089] In the context of a cancer, inhibition may be assessed by
inhibition of disease progression, inhibition of tumor growth,
reduction of primary tumor, relief of tumor-related symptoms,
inhibition of tumor secreted factors (including tumor secreted
hormones, such as those that contribute to carcinoid syndrome),
delayed appearance of primary or secondary tumors, slowed
development of primary or secondary tumors, decreased occurrence of
primary or secondary tumors, slowed or decreased severity of
secondary effects of disease, arrested tumor growth and regression
of tumors, increased Time To Progression (TTP), increased
Progression Free Survival (PFS), increased Overall Survival (OS),
among others. OS as used herein means the time from randomization
until death from any cause, and is measured in the intent-to-treat
population. TTP as used herein means the time from randomization
until objective tumor progression; TTP does not include deaths. As
used herein, PFS means the time from randomization until objective
tumor progression or death. In one embodiment, PFS rates will be
computed using the Kaplan-Meier estimates. In the extreme, complete
inhibition, is referred to herein as prevention or chemoprevention.
In this context, the term "prevention" includes either preventing
the onset of clinically evident advanced cancer altogether or
preventing the onset of a preclinically evident stage of a cancer.
Also intended to be encompassed by this definition is the
prevention of transformation into malignant cells or to arrest or
reverse the progression of premalignant cells to malignant cells.
This includes prophylactic treatment of those at risk of developing
a cancer.
[0090] In certain embodiments, the treatment of a cancer may be
assessed by Response Evaluation Criteria in Solid Tumors (RECIST
1.1) (see Thereasse P., et al. New Guidelines to Evaluate the
Response to Treatment in Solid Tumors. J. of the National Cancer
Institute; 2000; (92) 205-216 and Eisenhauer E. A., Therasse P.,
Bogaerts J., et al. New response evaluation criteria in solid
tumours: Revised RECIST guideline (version 1.1). European J.
Cancer; 2009; (45) 228-247). Overall responses for all possible
combinations of tumor responses in target and non-target lesions
with our without the appearance of new lesions are as follows:
TABLE-US-00001 Target lesions Non-target lesions New lesions
Overall response CR CR No CR CR Incomplete No PR response/SD PR
Non-PD No PR SD Non-PD No SD PD Any Yes or no PD Any PD Yes or no
PD Any Any Yes PD CR = complete response; PR = partial response; SD
= stable disease; and PD = progressive disease.
[0091] With respect to the evaluation of target lesions, complete
response (CR) is the disappearance of all target lesions, partial
response (PR) is at least a 30% decrease in the sum of the longest
diameter of target lesions, taking as reference the baseline sum
longest diameter, progressive disease (PD) is at least a 20%
increase in the sum of the longest diameter of target lesions,
taking as reference the smallest sum longest diameter recorded
since the treatment started or the appearance of one or more new
lesions and stable disease (SD) is neither sufficient shrinkage to
qualify for partial response nor sufficient increase to qualify for
progressive disease, taking as reference the smallest sum longest
diameter since the treatment started.
[0092] With respect to the evaluation of non-target lesions,
complete response (CR) is the disappearance of all non-target
lesions and normalization of tumor marker level; incomplete
response/stable disease (SD) is the persistence of one or more
non-target lesion(s) and/or the maintenance of tumor marker level
above the normal limits, and progressive disease (PD) is the
appearance of one or more new lesions and/or unequivocal
progression of existing non-target lesions.
[0093] In certain embodiments, treatment of a cancer may be
assessed by the inhibition of phosphorylation of S6RP, 4E-BP1, AKT
and/or DNA-PK in circulating blood and/or tumor cells, and/or skin
biopsies or tumor biopsies/aspirates, before, during and/or after
treatment with a Dihydropyrazino-Pyrazine Compound. For example,
the inhibition of phosphorylation of S6RP, 4E-BP1, AKT and/or
DNA-PK is assessed in B-cells, T-cells and/or monocytes. In other
embodiments, treatment of a cancer may be assessed by the
inhibition of DNA-dependent protein kinase (DNA-PK) activity in
skin samples and/or tumor biopsies/aspirates, such as by assessment
of the amount of pDNA-PK S2056 as a biomarker for DNA damage
pathways, before, during, and/or after Dihydropyrazino-Pyrazine
Compound treatment. In one embodiment, the skin sample is
irradiated by UV light.
[0094] In the extreme, complete inhibition, is referred to herein
as prevention or chemoprevention. In this context, the term
"prevention" includes either preventing the onset of clinically
evident cancer altogether or preventing the onset of a
preclinically evident stage of a cancer. Also intended to be
encompassed by this definition is the prevention of transformation
into malignant cells or to arrest or reverse the progression of
premalignant cells to malignant cells. This includes prophylactic
treatment of those at risk of developing a cancer.
5.2 Dihydropyrazino-Pyrazine Compounds
[0095] The compounds provided herein are generally referred to as
"Dihydropyrazino-Pyrazine Compound(s)."
[0096] In one embodiment, the Dihydropyrazino-Pyrazine Compounds
include compounds having the following formula (I):
##STR00002##
[0097] and pharmaceutically acceptable salts, clathrates, solvates,
stereoisomers, tautomers, metabolites, isotopologues and prodrugs
thereof, wherein:
[0098] R.sup.1 is substituted or unsubstituted C.sub.1-8 alkyl,
substituted or unsubstituted aryl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted heterocyclyl, or
substituted or unsubstituted heterocyclylalkyl;
[0099] R.sup.2 is H, substituted or unsubstituted C.sub.1-8 alkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted
heterocyclylalkyl, substituted or unsubstituted aralkyl, or
substituted or unsubstituted cycloalkylalkyl;
[0100] R.sup.3 is H, or a substituted or unsubstituted C.sub.1-8
alkyl,
[0101] wherein in certain embodiments, the Dihydropyrazino-Pyrazine
Compounds do not include
7-(4-hydroxyphenyl)-1-(3-methoxybenzyl)-3,4-dihydropyrazino[2,3-b]pyrazin-
-2(1H)-one, depicted below:
##STR00003##
[0102] In some embodiments of compounds of formula (I), R.sup.1 is
substituted or unsubstituted aryl or substituted or unsubstituted
heteroaryl. For example, R.sup.1 is phenyl, pyridyl, pyrimidyl,
benzimidazolyl, 1H-pyrrolo[2,3-b]pyridyl, indazolyl, indolyl,
1H-imidazo[4,5-b]pyridyl, 1H-imidazo[4,5-b]pyridin-2(3H)-onyl,
3H-imidazo[4,5-b]pyridyl, or pyrazolyl, each optionally
substituted. In some embodiments, R.sup.1 is phenyl substituted
with one or more substituents independently selected from the group
consisting of substituted or unsubstituted C.sub.1-8 alkyl (for
example, methyl), substituted or unsubstituted heterocyclyl (for
example, a substituted or unsubstituted triazolyl or pyrazolyl),
aminocarbonyl, halogen (for example, fluorine), cyano, hydroxyalkyl
and hydroxy. In other embodiments, R.sup.1 is pyridyl substituted
with one or more substituents independently selected from the group
consisting of substituted or unsubstituted C.sub.1-8 alkyl (for
example, methyl), substituted or unsubstituted heterocyclyl (for
example, a substituted or unsubstituted triazolyl), halogen,
aminocarbonyl, cyano, hydroxyalkyl (for example, hydroxypropyl),
--OR, and --NR.sub.2, wherein each R is independently H, or a
substituted or unsubstituted C.sub.1-4 alkyl. In some embodiments,
R.sup.1 is 1H-pyrrolo[2,3-b]pyridyl or benzimidazolyl, optionally
substituted with one or more substituents independently selected
from the group consisting of substituted or unsubstituted C.sub.1-8
alkyl, and --NR.sub.2, wherein R is independently H, or a
substituted or unsubstituted C.sub.1-4 alkyl.
[0103] In some embodiments, R.sup.1 is
##STR00004##
[0104] wherein R is at each occurrence independently H, or a
substituted or unsubstituted C.sub.1-4 alkyl (for example, methyl);
R' is at each occurrence independently a substituted or
unsubstituted C.sub.1-4 alkyl (for example, methyl), halogen (for
example, fluoro), cyano, --OR, or --NR.sub.2; m is 0-3; and n is
0-3. It will be understood by those skilled in the art that any of
the substitutents R' may be attached to any suitable atom of any of
the rings in the fused ring systems.
[0105] In some embodiments of compounds of formula (I), R.sup.1
is
##STR00005##
[0106] wherein R is at each occurrence independently H, or a
substituted or unsubstituted C.sub.1-4 alkyl; R' is at each
occurrence independently a substituted or unsubstituted C.sub.1-4
alkyl, halogen, cyano, --OR or --NR.sub.2; m is 0-3; and n is
0-3.
[0107] In some embodiments of compounds of formula (I), R.sup.2 is
H, substituted or unsubstituted C.sub.1-8 alkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
heterocyclyl, substituted or unsubstituted C.sub.1-4
alkyl-heterocyclyl, substituted or unsubstituted C.sub.1-4
alkyl-aryl, or substituted or unsubstituted C.sub.1-4
alkyl-cycloalkyl. For example, R.sup.2 is H, methyl, ethyl,
n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl,
n-pentyl, isopentyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl,
tetrahydropyranyl, (C.sub.1-4 alkyl)-phenyl, (C.sub.1-4
alkyl)-cyclopropyl, (C.sub.1-4 alkyl)-cyclobutyl, (C.sub.1-4
alkyl)-cyclopentyl, (C.sub.1-4 alkyl)-cyclohexyl, (C.sub.1-4
alkyl)-pyrrolidyl, (C.sub.1-4 alkyl)-piperidyl, (C.sub.1-4
alkyl)-piperazinyl, (C.sub.1-4 alkyl)-morpholinyl, (C.sub.1-4
alkyl)-tetrahydrofuranyl, or (C.sub.1-4 alkyl)-tetrahydropyranyl,
each optionally substituted.
[0108] In other embodiments, R.sup.2 is H, C.sub.1-4 alkyl,
(C.sub.1-4alkyl)(OR),
##STR00006##
[0109] wherein R is at each occurrence independently H, or a
substituted or unsubstituted C.sub.1-4 alkyl (for example, methyl);
R' is at each occurrence independently H, --OR, cyano, or a
substituted or unsubstituted C.sub.1-4 alkyl (for example, methyl);
and p is 0-3.
[0110] In other embodiments of compounds of formula (I), R.sup.2 is
H, C.sub.1-4 alkyl, (C.sub.1-4alkyl)(OR)
##STR00007##
[0111] wherein R is at each occurrence independently H, or a
substituted or unsubstituted C.sub.1-2 alkyl; R' is at each
occurrence independently H, --OR, cyano, or a substituted or
unsubstituted C.sub.1-2 alkyl; and p is 0-1.
[0112] In other embodiments of compounds of formula (I), R.sup.3 is
H.
[0113] In some such embodiments described herein, R.sup.1 is
substituted or unsubstituted aryl, or substituted or unsubstituted
heteroaryl. For example, R.sup.1 is phenyl, pyridyl, pyrimidyl,
benzimidazolyl, 1H-pyrrolo[2,3-b]pyridyl, indazolyl, indolyl,
1H-imidazo[4,5-b]pyridine, pyridyl,
1H-imidazo[4,5-b]pyridin-2(3H)-onyl, 3H-imidazo[4,5-b]pyridyl, or
pyrazolyl, each optionally substituted. In some embodiments,
R.sup.1 is phenyl substituted with one or more substituents
independently selected from the group consisting of substituted or
unsubstituted C.sub.1-8 alkyl, substituted or unsubstituted
heterocyclyl, aminocarbonyl, halogen, cyano, hydroxyalkyl and
hydroxy. In others, R.sup.1 is pyridyl substituted with one or more
substituents independently selected from the group consisting of
C.sub.1-8 alkyl, substituted or unsubstituted heterocyclyl,
halogen, aminocarbonyl, cyano, hydroxyalkyl, --OR, and --NR.sub.2,
wherein each R is independently H, or a substituted or
unsubstituted C.sub.1-4 alkyl. In still others, R.sup.1 is
1H-pyrrolo[2,3-b]pyridyl or benzimidazolyl, optionally substituted
with one or more substituents independently selected from the group
consisting of substituted or unsubstituted C.sub.1-8 alkyl, and
--NR.sub.2, wherein R is independently H, or a substituted or
unsubstituted C.sub.1-4 alkyl.
[0114] In certain embodiments, the compounds of formula (I) have an
R.sup.1 group set forth herein and an R.sup.2 group set forth
herein.
[0115] In some embodiments of compounds of formula (I), the
compound inhibits TOR kinase. In other embodiments of compounds of
formula (I), the compound inhibits DNA-PK. In certain embodiments
of compounds of formula (I), the compound inhibits both TOR kinase
and DNA-PK.
[0116] In some embodiments of compounds of formula (I), the
compound at a concentration of 10 .mu.M inhibits TOR kinase,
DNA-PK, PI3K, or a combination thereof by at least about 50%.
Compounds of formula (I) may be shown to be inhibitors of the
kinases above in any suitable assay system.
[0117] Representative Dihydropyrazino-Pyrazine Compounds of formula
(I) include compounds from Table A.
[0118] Table A. [0119]
7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-((trans-4-methoxy-
cyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;
[0120]
7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(cis-4-methoxycyclohexyl)-3,4-
-dihydropyrazino[2,3-b]pyrazin-2(1H)-one; [0121]
7-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3-
,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one; [0122]
7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-((cis-4-methoxycy-
clohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;
[0123]
1-ethyl-7-(1H-pyrrolo[3,2-b]pyridin-5-yl)-3,4-dihydropyrazino[2,3-b]pyraz-
in-2(1H)-one; [0124]
7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-((cis-4-methoxycyclohexyl)met-
hyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one; [0125]
7-(1H-benzo[d]imidazol-4-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-di-
hydropyrazino[2,3-b]pyrazin-2(1H)-one; [0126]
7-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3-
,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one; [0127]
7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-((trans-4-methoxycyclohexyl)m-
ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one; [0128]
7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-((trans-4-hydroxycyclohexyl)m-
ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one; [0129]
7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(cis-4-hydroxycyclohexyl)-3,4-
-dihydropyrazino[2,3-b]pyrazin-2(1H)-one; [0130]
7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-(cis-4-hydroxycyc-
lohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one; [0131]
7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-3,-
4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one; [0132]
7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(2-methoxyethyl)-3,4-dihydrop-
yrazino[2,3-b]pyrazin-2(1H)-one; [0133]
7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-ethyl-3,4-dihydropyrazino[2,3-
-b]pyrazin-2(1H)-one; [0134]
7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-((cis-4-hydroxycy-
clohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;
[0135]
7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-(tetrahydro-2H-py-
ran-4-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one; [0136]
7-(1H-indol-4-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazi-
no[2,3-b]pyrazin-2(1H)-one; [0137]
7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-((trans-4-hydroxy-
cyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;
[0138]
7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-((cis-4-hydroxycyclohexyl)met-
hyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one; [0139]
7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(trans-4-hydroxycyclohexyl)-3-
,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one; [0140]
7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(trans-4-methoxycyclohexyl)-3-
,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one; [0141]
7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-isopropyl-3,4-dihydropyrazino-
[2,3-b]pyrazin-2(1H)-one; [0142]
7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-(trans-4-methoxyc-
yclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one; [0143]
7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-(trans-4-hydroxyc-
yclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one; [0144]
7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-(2-methoxyethyl)--
3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one; [0145]
7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-isopropyl-3,4-dih-
ydropyrazino[2,3-b]pyrazin-2(1H)-one; [0146]
1-ethyl-7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-3,4-dihydro-
pyrazino[2,3-b]pyrazin-2(1H)-one; [0147]
7-(2-hydroxypyridin-4-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihyd-
ropyrazino[2,3-b]pyrazin-2(1H)-one; [0148]
1-isopropyl-7-(4-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydr-
opyrazino[2,3-b]pyrazin-2(1H)-one; [0149]
5-(8-isopropyl-7-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)-4-met-
hylpicolinamide; [0150]
7-(1H-indazol-4-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyra-
zino[2,3-b]pyrazin-2(1H)-one; [0151]
7-(2-aminopyrimidin-5-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihyd-
ropyrazino[2,3-b]pyrazin-2(1H)-one; [0152]
7-(2-aminopyridin-4-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydro-
pyrazino[2,3-b]pyrazin-2(1H)-one; [0153]
7-(6-(methylamino)pyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-
-dihydropyrazino[2,3-b]pyrazin-2(1H)-one; [0154]
7-(6-hydroxypyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihyd-
ropyrazino[2,3-b]pyrazin-2(1H)-one; [0155]
7-(4-(1H-pyrazol-3-yl)phenyl)-1-(2-methoxyethyl)-3,4-dihydropyrazino[2,3--
b]pyrazin-2(1H)-one; [0156]
7-(pyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazin-
o[2,3-b]pyrazin-2(1H)-one; [0157]
7-(1H-indazol-4-yl)-1-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin--
2(1H)-one; [0158]
7-(1H-indazol-6-yl)-1-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin--
2(1H)-one; [0159]
7-(pyrimidin-5-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyraz-
ino[2,3-b]pyrazin-2(1H)-one; [0160]
7-(6-methoxypyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihyd-
ropyrazino[2,3-b]pyrazin-2(1H)-one; [0161]
1-(2-methoxyethyl)-7-(1H-pyrrolo[2,3-b]pyridin-5-yl)-3,4-dihydropyrazino[-
2,3-b]pyrazin-2(1H)-one; [0162]
1-ethyl-7-(1H-pyrrolo[2,3-b]pyridin-5-yl)-3,4-dihydropyrazino[2,3-b]pyraz-
in-2(1H)-one; [0163]
1-ethyl-7-(1H-indazol-4-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;
[0164]
7-(pyridin-4-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydro-
pyrazino[2,3-b]pyrazin-2(1H)-one; [0165]
7-(6-aminopyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydro-
pyrazino[2,3-b]pyrazin-2(1H)-one; [0166]
1-methyl-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropy-
razino[2,3-b]pyrazin-2(1H)-one; [0167]
2-(2-hydroxypropan-2-yl)-5-(8-(trans-4-methoxycyclohexyl)-7-oxo-5,6,7,8-t-
etrahydropyrazino[2,3-b]pyrazin-2-yl)pyridine 1-oxide; [0168]
4-methyl-5-(7-oxo-8-((tetrahydro-2H-pyran-4-yl)methyl)-5,6,7,8-tetrahydro-
pyrazino[2,3-b]pyrazin-2-yl)picolinamide; [0169]
5-(8-((cis-4-methoxycyclohexyl)methyl)-7-oxo-5,6,7,8-tetrahydropyrazino[2-
,3-b]pyrazin-2-yl)-4-methylpicolinamide; [0170]
7-(1H-pyrazol-4-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyra-
zino[2,3-b]pyrazin-2(1H)-one; [0171]
1-(trans-4-methoxycyclohexyl)-7-(4-methyl-6-(1H-1,2,4-triazol-3-yl)pyridi-
n-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one; [0172]
3-(7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-2-oxo-3,4-dihydropy-
razino[2,3-b]pyrazin-1 (2H)-yl)methyl)benzonitrile; [0173]
1-((trans-4-methoxycyclohexyl)methyl)-7-(4-methyl-6-(1H-1,2,4-triazol-3-y-
l)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one; [0174]
3-(7-oxo-8-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-5,6,7,8-tetrahydropyrazino-
[2,3-b]pyrazin-2-yl)benzamide; [0175]
5-(8-((trans-4-methoxycyclohexyl)methyl)-7-oxo-5,6,7,8-tetrahydropyrazino-
[2,3-b]pyrazin-2-yl)-4-methylpicolinamide; [0176]
3-((7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-2-oxo-3,4-dihydropyrazino[2,-
3-b]pyrazin-1 (2H)-yl)methyl)benzonitrile; [0177]
7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((1R,3R)-3-methoxycyclopentyl)-
-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one; [0178]
7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((1S,3R)-3-methoxycyclopentyl)-
-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one; [0179]
7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((1S,3S)-3-methoxycyclopentyl)-
-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one; [0180]
7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((1R,3S)-3-methoxycyclopentyl)-
-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one; [0181]
7-(1H-indazol-6-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyra-
zino[2,3-b]pyrazin-2(1H)-one; [0182]
7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(2-morpholinoethyl)--
3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one; [0183]
1-(trans-4-hydroxycyclohexyl)-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridi-
n-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one; [0184]
1-(cis-4-hydroxycyclohexyl)-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin--
3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one; [0185]
7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(2-morpholinoethyl)-3,4-dihydr-
opyrazino[2,3-b]pyrazin-2(1H)-one; [0186]
1-isopropyl-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydr-
opyrazino[2,3-b]pyrazin-2(1H)-one; [0187]
7-(1H-imidazo[4,5-b]pyridin-6-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3-
,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one; [0188]
1-((cis-4-methoxycyclohexyl)methyl)-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)-
pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one; [0189]
1-(trans-4-hydroxycyclohexyl)-7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3,-
4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one; [0190]
1-(cis-4-hydroxycyclohexyl)-7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3,4--
dihydropyrazino[2,3-b]pyrazin-2(1H)-one; [0191]
4-(7-oxo-8-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-5,6,7,8-tetrahydropyrazino-
[2,3-b]pyrazin-2-yl)benzamide; [0192]
7-(1H-indazol-5-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyra-
zino[2,3-b]pyrazin-2(1H)-one; [0193]
7-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3-
,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one; [0194]
7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(tetrahydro-2H-pyran-
-4-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one; [0195]
1-((1S,3R)-3-methoxycyclopentyl)-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyr-
idin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one; [0196]
1-((1R,3R)-3-methoxycyclopentyl)-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyr-
idin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one; [0197]
1-((1R,3S)-3-methoxycyclopentyl)-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyr-
idin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one; [0198]
1-((1S,3S)-3-methoxycyclopentyl)-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyr-
idin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one; [0199]
7-(1H-indol-5-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazi-
no[2,3-b]pyrazin-2(1H)-one; [0200]
1-ethyl-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyr-
azino[2,3-b]pyrazin-2(1H)-one; [0201]
7-(1H-indol-6-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazi-
no[2,3-b]pyrazin-2(1H)-one; [0202]
7-(4-(2-hydroxypropan-2-yl)phenyl)-1-(trans-4-methoxycyclohexyl)-3,4-dihy-
dropyrazino[2,3-b]pyrazin-2(1H)-one; [0203]
7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-3,4-
-dihydropyrazino[2,3-b]pyrazin-2(1H)-one; [0204]
1-((trans-4-methoxycyclohexyl)methyl)-7-(2-methyl-6-(1H-1,2,4-triazol-3-y-
l)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one; [0205]
7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((cis-4-methoxycyclohexyl)meth-
yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one; [0206]
1-(2-methoxyethyl)-7-(4-methyl-2-(methylamino)-1H-benzo[d]imidazol-6-yl)--
3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one; [0207]
7-(7-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-1-((tetrahydro-2H-
-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;
[0208]
7-(2-methyl-4-(4H-1,2,4-triazol-3-yl)phenyl)-3,4-dihydropyrazino[2,3-b]py-
razin-2(1H)-one; [0209]
1-(2-methoxyethyl)-7-(4-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-
-dihydropyrazino[2,3-b]pyrazin-2(1H)-one; [0210]
1-benzyl-7-(2-methyl-4-(4H-1,2,4-triazol-3-yl)phenyl)-3,4-dihydropyrazino-
[2,3-b]pyrazin-2(1H)-one; [0211]
7-(3-fluoro-4-(4H-1,2,4-triazol-3-yl)phenyl)-1-(2-methoxyethyl)-3,4-dihyd-
ropyrazino[2,3-b]pyrazin-2(1H)-one; [0212]
7-(3-fluoro-4-(4H-1,2,4-triazol-3-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4--
yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one; [0213]
7-(3-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-(2-methoxyethyl)--
3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one; [0214]
1-(trans-4-methoxycyclohexyl)-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridi-
n-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one; [0215]
7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(trans-4-methoxycyclohexyl)-3,-
4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one; [0216]
7-(5-fluoro-2-methyl-4-(4H-1,2,4-triazol-3-yl)phenyl)-1-(2-(tetrahydro-2H-
-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;
[0217]
7-(3-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-(2-(tetrahydro-2H-
-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;
[0218]
1-(2-methoxyethyl)-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-
-dihydropyrazino[2,3-b]pyrazin-2(1H)-one; [0219]
7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((trans-4-methoxycyclohexyl)me-
thyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one; [0220]
1-(cyclopentylmethyl)-7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3,4-dihydr-
opyrazino[2,3-b]pyrazin-2(1H)-one; [0221]
7-(4-(2-hydroxypropan-2-yl)phenyl)-1-(2-methoxyethyl)-3,4-dihydropyrazino-
[2,3-b]pyrazin-2(1H)-one; [0222]
(S)-7-(6-(1-hydroxyethyl)pyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)eth-
yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one; [0223]
(R)-7-(6-(1-hydroxyethyl)pyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)eth-
yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one; [0224]
7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-((tetrahydro-2H-pyra-
n-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one; [0225]
7-(4-(2-hydroxypropan-2-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)--
3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one; [0226]
7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(4-(trifluoromethyl)benzyl)-3,-
4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one; [0227]
7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(3-(trifluoromethyl)benzyl)-3,-
4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one; [0228]
7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(3-methoxypropyl)-3,4-dihydrop-
yrazino[2,3-b]pyrazin-2(1H)-one; [0229]
7-(4-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(2-(tetrahydro-2H-py-
ran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one; [0230]
7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(2-methoxyethyl)-3,4-dihydropy-
razino[2,3-b]pyrazin-2(1H)-one; [0231]
7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((tetrahydro-2H-pyran-4-yl)met-
hyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one; [0232]
7-(4-methyl-2-(methylamino)-1H-benzo[d]imidazol-6-yl)-1-((tetrahydro-2H-p-
yran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;
[0233]
7-(2-amino-4-methyl-1H-benzo[d]imidazol-6-yl)-1-((tetrahydro-2H-pyran-4-y-
l)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one; [0234]
7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(2-(tetrahydro-2H-py-
ran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one; [0235]
(R)-7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3-methyl-1-(2-(tetrahydro-2H-
-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;
[0236]
(S)-7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3-methyl-1-(2-(tetrahydro-2H-
-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;
[0237]
7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3,3-dimethyl-1-(2-(tetrahydro-2H-
-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;
[0238]
7-(2-amino-4-methyl-1H-benzo[d]imidazol-6-yl)-1-(2-(tetrahydro-2H-pyran-4-
-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one; [0239]
7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)e-
thyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one; [0240]
7-(2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4--
yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;
[0241]
7-(4-(1H-1,2,4-triazol-5-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl-
)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one; [0242]
1-(1-hydroxypropan-2-yl)-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-y-
l)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one; and [0243]
1-(2-hydroxyethyl)-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-
-dihydropyrazino[2,3-b]pyrazin-2(1H)-one, and pharmaceutically
acceptable salts, clathrates, solvates, stereoisomers, tautomers,
metabolites, isotopologues and prodrugs thereof.
5.3 Methods for Making Dihydropyrazino-Pyrazine Compounds
[0244] The Dihydropyrazino-Pyrazine Compounds can be obtained via
standard, well-known synthetic methodology, see e.g., March, J.
Advanced Organic Chemistry; Reactions Mechanisms, and Structure,
4th ed., 1992. Starting materials useful for preparing compounds of
formula (III) and intermediates therefore, are commercially
available or can be prepared from commercially available materials
using known synthetic methods and reagents.
[0245] Particular methods for preparing compounds of formula (I)
are disclosed in U.S. Pat. No. 8,110,578, issued Feb. 7, 2012, and
U.S. Pat. No. 8,569,494, issued Oct. 29, 2013, each incorporated by
reference herein in their entirety.
5.4 Androgen Receptor Antagonists
[0246] In one embodiment, the androgen receptor antagonist is
enzalutamide (marketed as Xtandi.RTM., Astellas Pharma US, Inc.),
also known as and referred to herein as MDV3100, having the
chemical name
4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimida-
zolidin-1-yl)-2-fluoro-N-methylbenzamide and the structure:
##STR00008##
5.5 Methods of Use
[0247] Provided herein are methods for treating or preventing a
cancer comprising administering an effective amount of a
Dihydropyrazino-Pyrazine Compound and an effective amount of an
androgen receptor antagonist to a patient having a cancer.
[0248] In certain embodiments, the cancer is prostate cancer.
[0249] In other embodiments, the cancer is a solid tumor. In
certain embodiments, the solid tumor is a relapsed or refractory
solid tumor. In one embodiment, the cancer is metastatic. In
another, the cancer is hormone refractory. In yet another, the
cancer is an E-twenty six (ETS) overexpressing cancer.
[0250] In one embodiment, the solid tumor is an advanced solid
tumor.
[0251] In another embodiment, the cancer is E-twenty six (ETS)
overexpressing castration-resistant prostate cancer.
[0252] In other embodiments, the cancer is a cancer associated with
the pathways involving mTOR, PI3K, or Akt kinases and mutants or
isoforms thereof. Other cancers within the scope of the methods
provided herein include those associated with the pathways of the
following kinases: PI3K.beta., PI3K.beta., PI3K.delta., KDR,
GSK3.alpha., GSK3.beta., ATM, ATX, ATR, cFMS, and/or DNA-PK kinases
and mutants or isoforms thereof. In some embodiments, the cancers
associated with mTOR/PI3K/Akt pathways include solid tumors, for
example, prostate cancer.
[0253] In other embodiments, the cancer is metastatic
castration-resistant prostate cancer.
[0254] In other embodiments, the cancer is breast cancer.
[0255] In certain embodiments, provided herein are methods for
achieving a Response Evaluation Criteria in Solid Tumors (for
example, RECIST 1.1) of complete response, partial response or
stable disease in a patient having a solid tumor, comprising
administering an effective amount of a Dihydropyrazino-Pyrazine
Compound in combination with an androgen receptor antagonist to
said patient In certain embodiments, provided herein are methods
for achieving a Prostate Cancer Working Group 2 (PCWG2) Criteria of
complete response, partial response or stable disease in a patient
having prostate cancer, comprising administering an effective
amount of a Dihydropyrazino-Pyrazine Compound in combination with
an androgen receptor antagonist to said patient
[0256] In certain embodiments, provided herein are methods for
increasing survival without tumor progression of a patient having a
cancer, comprising administering an effective amount of a
Dihydropyrazino-Pyrazine Compound in combination with an effective
amount of an androgen receptor antagonist to said patient.
[0257] In one embodiment, provided herein are methods for
preventing or delaying a Response Evaluation Criteria in Solid
Tumors (for example, RECIST 1.1) of progressive disease in a
patient, comprising administering an effective amount of a
Dihydropyrazino-Pyrazine Compound in combination with an effective
amount of an androgen receptor antagonist to a patient having a
cancer. In one embodiment the prevention or delaying of progressive
disease is characterized or achieved by a change in overall size of
the target lesions, of for example, between -30% and +20% compared
to pre-treatment. In another embodiment, the change in size of the
target lesions is a reduction in overall size of more than 30%, for
example, more than 50% reduction in target lesion size compared to
pre-treatment. In another, the prevention is characterized or
achieved by a reduction in size or a delay in progression of
non-target lesions compared to pre-treatment. In one embodiment,
the prevention is achieved or characterized by a reduction in the
number of target lesions compared to pre-treatment. In another, the
prevention is achieved or characterized by a reduction in the
number or quality of non-target lesions compared to pre-treatment.
In one embodiment, the prevention is achieved or characterized by
the absence or the disappearance of target lesions compared to
pre-treatment. In another, the prevention is achieved or
characterized by the absence or the disappearance of non-target
lesions compared to pre-treatment. In another embodiment, the
prevention is achieved or characterized by the prevention of new
lesions compared to pre-treatment. In yet another embodiment, the
prevention is achieved or characterized by the prevention of
clinical signs or symptoms of disease progression compared to
pre-treatment, such as cancer-related cachexia or increased
pain.
[0258] In certain embodiments, provided herein are methods for
decreasing the size of target lesions in a patient compared to
pre-treatment, comprising administering an effective amount of a
Dihydropyrazino-Pyrazine Compound in combination with an effective
amount of an androgen receptor antagonist to a patient having a
cancer.
[0259] In certain embodiments, provided herein are methods for
decreasing the size of a non-target lesion in a patient compared to
pre-treatment, comprising administering an effective amount of a
Dihydropyrazino-Pyrazine Compound in combination with an effective
amount of an androgen receptor antagonist to a patient having a
cancer.
[0260] In certain embodiments, provided herein are methods for
achieving a reduction in the number of target lesions in a patient
compared to pre-treatment, comprising administering an effective
amount of a Dihydropyrazino-Pyrazine Compound in combination with
an effective amount of an androgen receptor antagonist to a patient
having a cancer.
[0261] In certain embodiments, provided herein are methods for
achieving a reduction in the number of non-target lesions in a
patient compared to pre-treatment, comprising administering an
effective amount of a Dihydropyrazino-Pyrazine Compound in
combination with an effective amount of an androgen receptor
antagonist to a patient having a cancer.
[0262] In certain embodiments, provided herein are methods for
achieving an absence of all target lesions in a patient, comprising
administering an effective amount of a Dihydropyrazino-Pyrazine
Compound in combination with an effective amount of an androgen
receptor antagonist to a patient having a cancer.
[0263] In certain embodiments, provided herein are methods for
achieving an absence of all non-target lesions in a patient,
comprising administering an effective amount of a
Dihydropyrazino-Pyrazine Compound in combination with an effective
amount of an androgen receptor antagonist to a patient having a
cancer.
[0264] In certain embodiments, provided herein are methods for
treating a cancer, the methods comprising administering an
effective amount of a Dihydropyrazino-Pyrazine Compound in
combination with an effective amount of an androgen receptor
antagonist to a patient having a cancer, wherein the treatment
results in a complete response, partial response or stable disease,
as determined by Response Evaluation Criteria in Solid Tumors (for
example, RECIST 1.1).
[0265] In certain embodiments, provided herein are methods for
treating a cancer, the methods comprising administering an
effective amount of a Dihydropyrazino-Pyrazine Compound in
combination with an effective amount of an androgen receptor
antagonist to a patient having a cancer, wherein the treatment
results in a reduction in target lesion size, a reduction in
non-target lesion size and/or the absence of new target and/or
non-target lesions, compared to pre-treatment.
[0266] In certain embodiments, provided herein are methods for
treating a cancer, the methods comprising administering an
effective amount of a Dihydropyrazino-Pyrazine Compound in
combination with an effective amount of an androgen receptor
antagonist to a patient having a cancer, wherein the treatment
results in prevention or retarding of clinical progression, such as
cancer-related cachexia or increased pain.
[0267] In some embodiments, provided herein are methods for
treating a cancer, the methods comprising administering an
effective amount of a Dihydropyrazino-Pyrazine Compound in
combination with an effective amount of an androgen receptor
antagonist to a patient having a cancer, wherein the treatment
results in one or more of inhibition of disease progression,
inhibition of tumor growth, reduction of primary tumor, relief of
tumor-related symptoms, inhibition of tumor secreted factors
(including tumor secreted hormones, such as those that contribute
to carcinoid syndrome), delayed appearance of primary or secondary
tumors, slowed development of primary or secondary tumors,
decreased occurrence of primary or secondary tumors, slowed or
decreased severity of secondary effects of disease, arrested tumor
growth and regression of tumors, increased Time To Progression
(TTP), increased Progression Free Survival (PFS), and/or increased
Overall Survival (OS), among others.
[0268] In some embodiments, the Dihydropyrazino-Pyrazine Compound
is a compound as described herein. In one embodiment, the
Dihydropyrazino-Pyrazine Compound is a compound of formula (I). In
one embodiment, the Dihydropyrazino-Pyrazine Compound is a compound
from Table A. In one embodiment, the Dihydropyrazino-Pyrazine
Compound is Compound 1 (a Dihydropyrazino-Pyrazine Compound set
forth herein having molecular formula
C.sub.21H.sub.27N.sub.5O.sub.3). In one embodiment, the
Dihydropyrazino-Pyrazine Compound is Compound 2 (a
Dihydropyrazino-Pyrazine Compound set forth herein having molecular
formula C.sub.16H.sub.16N.sub.8O). In one embodiment, the
Dihydropyrazino-Pyrazine Compound is Compound 3 (a
Dihydropyrazino-Pyrazine Compound set forth herein having molecular
formula C.sub.20H.sub.25N.sub.5O.sub.3). In one embodiment,
Compound 1 is
7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((1r,4r)-4-methoxycyclohexyl)--
3,4-dihydropyrazino-[2,3-b]pyrazin-2(1H)-one, alternatively named
7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((trans)-4-methoxycyclohexyl)--
3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one, or
7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((1R*,4R*)-4-methoxycyclohexyl-
)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one. In another
embodiment, Compound 2 is
1-ethyl-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyr-
azino[2,3-b]pyrazin-2(1H)-one, or a tautomer thereof, for example,
1-ethyl-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyr-
azino[2,3-b]pyrazin-2(1H)-one, or
1-ethyl-7-(2-methyl-6-(1H-1,2,4-triazol-5-yl)pyridin-3-yl)-3,4-dihydropyr-
azino[2,3-b]pyrazin-2(1H)-one. In another embodiment, Compound 3 is
1-((trans)-4-hydroxycyclohexyl)-7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)--
3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one, alternatively named
1-((1r,4r)-4-hydroxycyclohexyl)-7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)--
3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one. In one embodiment,
Compound 3 is a metabolite of Compound 1.
[0269] In one embodiment, the androgen receptor antagonist is
MDV-3100.
[0270] A Dihydropyrazino-Pyrazine Compound administered in
combination with an androgen receptor antagonist can be further
combined with radiation therapy or surgery. In certain embodiments,
a Dihydropyrazino-Pyrazine Compound is administered in combination
with an androgen receptor antagonist to patient who is undergoing
radiation therapy, has previously undergone radiation therapy or
will be undergoing radiation therapy. In certain embodiments, a
Dihydropyrazino-Pyrazine Compound is administered in combination
with an androgen receptor antagonist to a patient who has undergone
surgery, such as tumor removal surgery.
[0271] Further provided herein are methods for treating patients
who have been previously treated for a cancer, as well as those who
have not previously been treated. Further provided herein are
methods for treating patients who have undergone surgery in an
attempt to treat a cancer, as well as those who have not. Because
patients with a cancer have heterogenous clinical manifestations
and varying clinical outcomes, the treatment given to a patient may
vary, depending on his/her prognosis. The skilled clinician will be
able to readily determine without undue experimentation specific
secondary agents, types of surgery, and types of non-drug based
standard therapy that can be effectively used to treat an
individual patient with a cancer.
[0272] In certain embodiments, a Dihydropyrazino-Pyrazine Compound
is administered in combination with an androgen receptor antagonist
to a patient in cycles. Cycling therapy involves the administration
of an active agent(s) for a period of time, followed by a rest for
a period of time, and repeating this sequential administration.
Cycling therapy can reduce the development of resistance, avoid or
reduce the side effects, and/or improves the efficacy of the
treatment.
[0273] In one embodiment, a Dihydropyrazino-Pyrazine Compound is
administered in combination with an androgen receptor antagonist
daily in single or divided doses for about 3 days, about 5 days,
about one week, about two weeks, about three weeks, about four
weeks (e.g., 28 days), about five weeks, about six weeks, about
seven weeks, about eight weeks, about ten weeks, about fifteen
weeks, or about twenty weeks, followed by a rest period of about 1
day to about ten weeks. In one embodiment, the methods provided
herein contemplate cycling treatments of about one week, about two
weeks, about three weeks, about four weeks, about five weeks, about
six weeks, about eight weeks, about ten weeks, about fifteen weeks,
or about twenty weeks. In some embodiments, a
Dihydropyrazino-Pyrazine Compound is administered in combination
with an androgen receptor antagonist in single or divided doses for
about 3 days, about 5 days, about one week, about two weeks, about
three weeks, about four weeks (e.g., 28 days), about five weeks, or
about six weeks with a rest period of about 1, 2, 3, 4, 5, 6, 7, 8,
9, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 29, or 30 days. In some
embodiments, the rest period is 1 day. In some embodiments, the
rest period is 3 days. In some embodiments, the rest period is 7
days. In some embodiments, the rest period is 14 days. In some
embodiments, the rest period is 28 days. The frequency, number and
length of dosing cycles can be increased or decreased.
[0274] In one embodiment, the methods provided herein comprise: i)
administering to the subject a first daily dose of a
Dihydropyrazino-Pyrazine Compound in combination with an androgen
receptor antagonist; ii) optionally resting for a period of at
least one day where an androgen receptor antagonist is not
administered to the subject; iii) administering a second dose of a
Dihydropyrazino-Pyrazine Compound in combination with an androgen
receptor antagonist to the subject; and iv) repeating steps ii) to
iii) a plurality of times.
[0275] In one embodiment, the methods provided herein comprise
administering to the subject a dose of an androgen receptor
antagonist on day 1, followed by administering a
Dihydropyrazino-Pyrazine Compound in combination with an androgen
receptor antagonist to the subject on day 2 and subsequent
days.
[0276] In certain embodiments, a Dihydropyrazino-Pyrazine Compound
in combination with an androgen receptor antagonist is administered
continuously for between about 1 and about 52 weeks. In certain
embodiments, a Dihydropyrazino-Pyrazine Compound in combination
with an androgen receptor antagonist is administered continuously
for about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months. In
certain embodiments, a Dihydropyrazino-Pyrazine Compound in
combination with an androgen receptor antagonist is administered
continuously for about 7, about 14, about 21, about 28, about 35,
about 42, about 84, or about 112 days.
[0277] In certain embodiments, when a Dihydropyrazino-Pyrazine
Compound is administered in combination with an androgen receptor
antagonist the Dihydropyrazino-Pyrazine Compound is administered at
an amount of about 2.5 mg to about 50 mg per day (such as about 0.5
mg, 1 mg, 2 mg, 4 mg, 8 mg, 10 mg, 15 mg, 16 mg, 20 mg, 25 mg, 30
mg, 45 mg, 60 mg, 90 mg, 120 mg or 128 mg per day) and an androgen
receptor antagonist is administered at an amount of about 50 mg to
about 200 mg per day (such as about 80 mg, about 120 mg or about
160 mg per day). In certain embodiments, about 2.5 mg per day of a
Dihydropyrazino-Pyrazine Compound is administered in combination
with about 80 mg, about 120 mg or about 160 mg per day of an
androgen receptor antagonist. In certain embodiments, about 10 mg
per day of a Dihydropyrazino-Pyrazine Compound is administered in
combination with about 80 mg, about 120 mg or about 160 mg per day
of an androgen receptor antagonist. In certain embodiments, about
15 mg per day of a Dihydropyrazino-Pyrazine Compound is
administered in combination with about 80 mg, about 120 mg or about
160 mg per day of an androgen receptor antagonist. In certain
embodiments, about 16 mg per day of a Dihydropyrazino-Pyrazine
Compound is administered in combination with about 80 mg, about 120
mg or about 160 mg per day of an androgen receptor antagonist. In
certain embodiments, about 20 mg per day of a
Dihydropyrazino-Pyrazine Compound is administered in combination
with about 80 mg, about 120 mg or about 160 mg per day of an
androgen receptor antagonist. In certain embodiments, about 25 mg
per day of a Dihydropyrazino-Pyrazine Compound is administered in
combination with about 80 mg, about 120 mg or about 160 mg per day
of an androgen receptor antagonist. In certain embodiments, about
30 mg per day of a Dihydropyrazino-Pyrazine Compound is
administered in combination with about 80 mg, about 120 mg or about
160 mg per day of an androgen receptor antagonist. In certain
embodiments, about 45 mg per day of a Dihydropyrazino-Pyrazine
Compound is administered in combination with about 80 mg, about 120
mg or about 160 mg per day of an androgen receptor antagonist. In
certain embodiments, when an androgen receptor antagonist is
administered in combination with a Dihydropyrazino-Pyrazine
Compound, the androgen receptor antagonist is administered as four
discrete capsules. For example, when a dose of 160 mg per day of an
androgen receptor antagonist is administered in combination with a
Dihydropyrazino-Pyrazine Compound, it can be administered as four
40 mg capsules. A Dihydropyrazino-Pyrazine Compound and an androgen
receptor antagonist can each be independently administered once
(QD), twice (BD), three times (TID) or four times per day.
[0278] In certain embodiments, when a Dihydropyrazino-Pyrazine
Compound is administered in combination with an androgen receptor
antagonist, the Dihydropyrazino-Pyrazine Compound:androgen receptor
antagonist ratio is from about 1:1 to about 1:10. In certain
embodiments, when a Dihydropyrazino-Pyrazine Compound is
administered in combination with an androgen receptor antagonist,
the Dihydropyrazino-Pyrazine Compound:androgen receptor antagonist
ratio is less than about 1:1, less than about 1:3 or less than
about 1:10. In certain embodiments, when a Dihydropyrazino-Pyrazine
Compound is administered in combination with an androgen receptor
antagonist, the Dihydropyrazino-Pyrazine Compound:androgen receptor
antagonist ratio is about 1:1, about 1:3 or about 1:10.
[0279] In certain embodiments, when a Dihydropyrazino-Pyrazine
Compound is administered in combination with an androgen receptor
antagonist, the Dihydropyrazino-Pyrazine Compound:androgen receptor
antagonist ratio is from about 1:1 to about 1:30. In certain
embodiments, when a Dihydropyrazino-Pyrazine Compound is
administered in combination with an androgen receptor antagonist,
the Dihydropyrazino-Pyrazine Compound:androgen receptor antagonist
ratio is less than about 1:1, less than about 1:10 or less than
about 1:30. In certain embodiments, when a Dihydropyrazino-Pyrazine
Compound is administered in combination with an androgen receptor
antagonist, the Dihydropyrazino-Pyrazine Compound:androgen receptor
antagonist ratio is about 1:1, about 1:10 or about 1:30.
5.6 Pharmaceutical Compositions and Routes of Administration
[0280] Provided herein are compositions comprising an effective
amount of a Dihydropyrazino-Pyrazine Compound and an effective
amount of an androgen receptor antagonist and compositions,
comprising an effective amount of a Dihydropyrazino-Pyrazine
Compound and an androgen receptor antagonist and a pharmaceutically
acceptable carrier or vehicle.
[0281] In some embodiments, the pharmaceutical compositions
described herein are suitable for oral, parenteral, mucosal,
transdermal or topical administration.
[0282] The compositions can be administered to a patient orally or
parenterally in the conventional form of preparations, such as
capsules, microcapsules, tablets, granules, powder, troches, pills,
suppositories, injections, suspensions and syrups. Suitable
formulations can be prepared by methods commonly employed using
conventional, organic or inorganic additives, such as an excipient
(e.g., sucrose, starch, mannitol, sorbitol, lactose, glucose,
cellulose, talc, calcium phosphate or calcium carbonate), a binder
(e.g., cellulose, methylcellulose, hydroxymethylcellulose,
polypropylpyrrolidone, polyvinylpyrrolidone, gelatin, gum arabic,
polyethyleneglycol, sucrose or starch), a disintegrator (e.g.,
starch, carboxymethylcellulose, hydroxypropylstarch, low
substituted hydroxypropylcellulose, sodium bicarbonate, calcium
phosphate or calcium citrate), a lubricant (e.g., magnesium
stearate, light anhydrous silicic acid, talc or sodium lauryl
sulfate), a flavoring agent (e.g., citric acid, menthol, glycine or
orange powder), a preservative (e.g, sodium benzoate, sodium
bisulfite, methylparaben or propylparaben), a stabilizer (e.g.,
citric acid, sodium citrate or acetic acid), a suspending agent
(e.g., methylcellulose, polyvinyl pyrroliclone or aluminum
stearate), a dispersing agent (e.g., hydroxypropylmethylcellulose),
a diluent (e.g., water), and base wax (e.g., cocoa butter, white
petrolatum or polyethylene glycol). The effective amount of the
Dihydropyrazino-Pyrazine Compound in the pharmaceutical composition
may be at a level that will exercise the desired effect; for
example, about 0.005 mg/kg of a patient's body weight to about 10
mg/kg of a patient's body weight in unit dosage for both oral and
parenteral administration.
[0283] The dose of a Dihydropyrazino-Pyrazine Compound and the dose
of an androgen receptor antagonist to be administered to a patient
is rather widely variable and can be subject to the judgment of a
health-care practitioner. In general, the Dihydropyrazino-Pyrazine
Compounds and an androgen receptor antagonist can be administered
one to four times a day in a dose of about 0.005 mg/kg of a
patient's body weight to about 10 mg/kg of a patient's body weight
in a patient, but the above dosage may be properly varied depending
on the age, body weight and medical condition of the patient and
the type of administration. In one embodiment, the dose is about
0.01 mg/kg of a patient's body weight to about 5 mg/kg of a
patient's body weight, about 0.05 mg/kg of a patient's body weight
to about 1 mg/kg of a patient's body weight, about 0.1 mg/kg of a
patient's body weight to about 0.75 mg/kg of a patient's body
weight or about 0.25 mg/kg of a patient's body weight to about 0.5
mg/kg of a patient's body weight. In one embodiment, one dose is
given per day. In any given case, the amount of the
Dihydropyrazino-Pyrazine Compound administered will depend on such
factors as the solubility of the active component, the formulation
used and the route of administration.
[0284] In another embodiment, provided herein are unit dosage
formulations that comprise between about 1 mg and about 2000 mg,
about 1 mg and about 200 mg, about 35 mg and about 1400 mg, about
125 mg and about 1000 mg, about 250 mg and about 1000 mg, about 500
mg and about 1000 mg, about 1 mg to about 30 mg, about 1 mg to
about 25 mg or about 2.5 mg to about 20 mg of a
Dihydropyrazino-Pyrazine Compound alone or in combination with an
androgen receptor antagonist. In another embodiment, provided
herein are unit dosage formulations that comprise 1 mg, 2.5 mg, 5
mg, 7.5 mg, 8 mg, 10 mg, 15 mg, 20 mg, 30 mg, 35 mg, 45 mg, 50 mg,
70 mg, 100 mg, 125 mg, 140 mg, 175 mg, 200 mg, 250 mg, 280 mg, 350
mg, 500 mg, 560 mg, 700 mg, 750 mg, 1000 mg or 1400 mg of a
Dihydropyrazino-Pyrazine Compound alone or in combination with an
androgen receptor antagonist. In another embodiment, provided
herein are unit dosage formulations that comprise about 2.5 mg,
about 10 mg, about 15 mg, about 20 mg, about 30 mg or about 45 mg
of a Dihydropyrazino-Pyrazine Compound alone or in combination with
an androgen receptor antagonist. In a particular embodiment,
provided herein are unit dosage formulations that comprise about 5
mg, about 7.5 mg and about 10 mg of a Dihydropyrazino-Pyrazine
Compound alone or in combination with an androgen receptor
antagonist.
[0285] In a particular embodiment, provided herein are unit dosage
formulations comprising about 10 mg, about 15 mg, about 30 mg,
about 45 mg, about 50 mg, about 75 mg, about 100 mg or about 400 mg
of a Dihydropyrazino-Pyrazine Compound in combination with an
androgen receptor antagonist.
[0286] In a particular embodiment, provided herein are unit dosage
formulations comprising about 20 mg to about 60 mg of an androgen
receptor antagonist in combination with a Dihydropyrazino-Pyrazine
Compound. In a particular embodiment, provided herein are unit
dosage formulations comprising about 40 mg of an androgen receptor
antagonist in combination with a Dihydropyrazino-Pyrazine
Compound.
[0287] In certain embodiments, provided herein are unit dosage
formulations wherein the Dihydropyrazino-Pyrazine Compound:androgen
receptor antagonist ratio is from about 1:1 to about 1:10. In
certain embodiments, provided herein are unit dosage formulations
wherein the Dihydropyrazino-Pyrazine Compound:androgen receptor
antagonist ratio is less than about 1:1, less than about 1:3 or
less than about 1:10. In certain embodiments, provided herein are
unit dosage formulations wherein the Dihydropyrazino-Pyrazine
Compound:androgen receptor antagonist ratio is about 1:1, about 1:3
or about 1:10.
[0288] A Dihydropyrazino-Pyrazine Compound can be administered in
combination with an androgen receptor antagonist once, twice,
three, four or more times daily.
[0289] A Dihydropyrazino-Pyrazine Compound can be administered in
combination with an androgen receptor antagonist orally for reasons
of convenience. In one embodiment, when administered orally, a
Dihydropyrazino-Pyrazine Compound in combination with an androgen
receptor antagonist is administered with a meal and water. In
another embodiment, the Dihydropyrazino-Pyrazine Compound in
combination with an androgen receptor antagonist is dispersed in
water or juice (e.g., apple juice or orange juice) and administered
orally as a suspension. In another embodiment, when administered
orally, a Dihydropyrazino-Pyrazine Compound in combination with an
androgen receptor antagonist is administered in a fasted state.
[0290] The Dihydropyrazino-Pyrazine Compound can also be
administered in combination with an androgen receptor antagonist
intravenously, such as intravenous infusion, or subcutaneously,
such as subcutaneous injection. The mode of administration is left
to the discretion of the health-care practitioner, and can depend
in-part upon the site of the medical condition.
[0291] In one embodiment, provided herein are capsules containing a
Dihydropyrazino-Pyrazine Compound in combination with an androgen
receptor antagonist without an additional carrier, excipient or
vehicle.
[0292] In another embodiment, provided herein are compositions
comprising an effective amount of a Dihydropyrazino-Pyrazine
Compound, an effective amount of an androgen receptor antagonist,
and a pharmaceutically acceptable carrier or vehicle, wherein a
pharmaceutically acceptable carrier or vehicle can comprise an
excipient, diluent, or a mixture thereof. In one embodiment, the
composition is a pharmaceutical composition.
[0293] The compositions can be in the form of tablets, chewable
tablets, capsules, solutions, parenteral solutions, troches,
suppositories and suspensions and the like. Compositions can be
formulated to contain a daily dose, or a convenient fraction of a
daily dose, in a dosage unit, which may be a single tablet or
capsule or convenient volume of a liquid. In one embodiment, the
solutions are prepared from water-soluble salts, such as the
hydrochloride salt. In general, all of the compositions are
prepared according to known methods in pharmaceutical chemistry.
Capsules can be prepared by mixing a Dihydropyrazino-Pyrazine
Compound with a suitable carrier or diluent and filling the proper
amount of the mixture in capsules. The usual carriers and diluents
include, but are not limited to, inert powdered substances such as
starch of many different kinds, powdered cellulose, especially
crystalline and microcrystalline cellulose, sugars such as
fructose, mannitol and sucrose, grain flours and similar edible
powders.
[0294] Tablets can be prepared by direct compression, by wet
granulation, or by dry granulation. Their formulations usually
incorporate diluents, binders, lubricants and disintegrators as
well as the compound. Typical diluents include, for example,
various types of starch, lactose, mannitol, kaolin, calcium
phosphate or sulfate, inorganic salts such as sodium chloride and
powdered sugar. Powdered cellulose derivatives are also useful. In
one embodiment, the pharmaceutical composition is lactose-free.
Typical tablet binders are substances such as starch, gelatin and
sugars such as lactose, fructose, glucose and the like. Natural and
synthetic gums are also convenient, including acacia, alginates,
methylcellulose, polyvinylpyrrolidine and the like. Polyethylene
glycol, ethylcellulose and waxes can also serve as binders.
Illustrative tablet formulations comprising Compound 2 are provided
herein.
[0295] A lubricant might be necessary in a tablet formulation to
prevent the tablet and punches from sticking in the die. The
lubricant can be chosen from such slippery solids as talc,
magnesium and calcium stearate, stearic acid and hydrogenated
vegetable oils. Tablet disintegrators are substances that swell
when wetted to break up the tablet and release the compound. They
include starches, clays, celluloses, algins and gums. More
particularly, corn and potato starches, methylcellulose, agar,
bentonite, wood cellulose, powdered natural sponge, cation-exchange
resins, alginic acid, guar gum, citrus pulp and carboxymethyl
cellulose, for example, can be used as well as sodium lauryl
sulfate. Tablets can be coated with sugar as a flavor and sealant,
or with film-forming protecting agents to modify the dissolution
properties of the tablet. The compositions can also be formulated
as chewable tablets, for example, by using substances such as
mannitol in the formulation.
[0296] When it is desired to administer a Dihydropyrazino-Pyrazine
Compound in combination with an androgen receptor antagonist as a
suppository, typical bases can be used. Cocoa butter is a
traditional suppository base, which can be modified by addition of
waxes to raise its melting point slightly. Water-miscible
suppository bases comprising, particularly, polyethylene glycols of
various molecular weights are in wide use.
[0297] The effect of the Dihydropyrazino-Pyrazine Compound in
combination with an androgen receptor antagonist can be delayed or
prolonged by proper formulation. For example, a slowly soluble
pellet of the Dihydropyrazino-Pyrazine Compound in combination with
an androgen receptor antagonist can be prepared and incorporated in
a tablet or capsule, or as a slow-release implantable device. The
technique also includes making pellets of several different
dissolution rates and filling capsules with a mixture of the
pellets. Tablets or capsules can be coated with a film that resists
dissolution for a predictable period of time. Even the parenteral
preparations can be made long-acting, by dissolving or suspending
the Dihydropyrazino-Pyrazine Compound in combination with an
androgen receptor antagonist in oily or emulsified vehicles that
allow it to disperse slowly in the serum.
[0298] In certain embodiments, the Dihydropyrazino-Pyrazine
Compound is administered in a formulation set forth in U.S. Patent
Application Publication No. 2013-0142873, published Jun. 6, 2013,
which is incorporated herein in its entirety (see particularly
paragraph [0323] to paragraph [0424], and paragraph [0636] to
paragraph [0655]). In other embodiments, the
Dihydropyrazino-Pyrazine Compound is administered in a formulation
set forth in U.S. Provisional Patent Application No. 61/828,506,
filed May 29, 2013, which is incorporated herein in its entirety
(see particularly paragraph [0246] to paragraph [0403], and
paragraph [0571] to paragraph [0586]).
[0299] In certain embodiments, the Dihydropyrazino-Pyrazine
Compound is administered in a formulation set forth in U.S.
Provisional Application No. 61/813,064, filed Apr. 17, 2013, which
is incorporated herein in its entirety (see particularly paragraph
[0168] to paragraph [0189] and paragraph [0262] to paragraph
[0294]). In other embodiments, the Dihydropyrazino-Pyrazine
Compound is administered in a formulation set forth in U.S.
Provisional Patent Application No. 61/911,201, filed Dec. 3, 2013,
which is incorporated herein in its entirety (see particularly
paragraph [0170] to paragraph [0190], and paragraph [0264] to
paragraph [0296]).
5.7 Kits
[0300] In certain embodiments, provided herein are kits comprising
a Dihydropyrazino-Pyrazine Compound and an androgen receptor
antagonist.
[0301] In certain embodiments, provided herein are kits comprising
one or more unit dosage forms of a Dihydropyrazino-Pyrazine
Compound, such as those described herein, and one or more unit
dosage forms of an androgen receptor antagonist, such as those
described herein.
[0302] In certain embodiments, the kits provided herein further
comprise instructions for use, such as for administering a
Dihydropyrazino-Pyrazine Compound and an androgen receptor
antagonist.
6. EXAMPLES
6.1 Biochemical Assays
[0303] mTOR HTR-FRET Assay.
[0304] The following is an example of an assay that can be used to
determine the TOR kinase inhibitory activity of a test compound.
Dihydropyrazino-Pyrazine Compounds were dissolved in DMSO and
prepared as 10 mM stocks and diluted appropriately for the
experiments. Reagents were prepared as follows:
[0305] "Simple TOR buffer" (used to dilute high glycerol TOR
fraction): 10 mM Tris pH 7.4, 100 mM NaCl, 0.1% Tween-20, 1 mM DTT.
Invitrogen mTOR (cat#PV4753) was diluted in this buffer to an assay
concentration of 0.200 .mu.g/mL.
[0306] ATP/Substrate solution: 0.075 mM ATP, 12.5 mM MnCl.sub.2, 50
mM Hepes, pH 7.4, 50 mM .beta.-GOP, 250 nM Microcystin LR, 0.25 mM
EDTA, 5 mM DTT, and 3.5 .mu.g/mL GST-p70S6.
[0307] Detection reagent solution: 50 mM HEPES, pH 7.4, 0.01%
Triton X-100, 0.01% BSA, 0.1 mM EDTA, 12.7 .mu.g/mL Cy5-.alpha.GST
Amersham (Cat#PA92002V), 9 ng/mL .alpha.-phospho p70S6 (Thr389)
(Cell Signaling Mouse Monoclonal #9206L), 627 ng/mL .alpha.-mouse
Lance Eu (Perkin Elmer Cat#AD0077).
[0308] To 20 .mu.L of the Simple TOR buffer is added 0.5 .mu.L of
test compound in DMSO. To initiate the reaction 5 .mu.L of
ATP/Substrate solution was added to 20 .mu.L of the Simple TOR
buffer solution (control) and to the compound solution prepared
above. The assay was stopped after 60 min by adding 5 .mu.L of a 60
mM EDTA solution; 10 .mu.L of detection reagent solution was then
added and the mixture was allowed to sit for at least 2 hours
before reading on a Perkin-Elmer Envision Microplate Reader set to
detect LANCE Eu TR-FRET (excitation at 320 nm and emission at
495/520 nm).
[0309] Dihydropyrazino-Pyrazine Compounds were tested in the mTOR
HTR-FRET assay and were found to have activity therein, with
certain compounds having an IC.sub.50 below 10 .mu.M in the assay,
with some compounds having an IC.sub.50 between and 0.005 nM and
250 nM, others having an IC.sub.50 between and 250 nM and 500 nM,
others having an IC.sub.50 between 500 nM and 1 .mu.M, and others
having an IC.sub.50 between 1 .mu.M and 10 .mu.M.
[0310] DNA-PK Assay.
[0311] DNA-PK assay is performed using the procedures supplied in
the Promega DNA-PK assay kit (catalog #V7870). DNA-PK enzyme can be
purchased from Promega (Promega cat#V5811).
[0312] Selected Dihydropyrazino-Pyrazine Compounds as described
herein have, or are expected to have, an IC.sub.50 below 10 .mu.M
in this assay, with some Dihydropyrazino-Pyrazine Compounds as
described herein having an IC.sub.50 below 1 .mu.M, and others
having an IC.sub.50 below 0.10 .mu.M.
6.2 Cell Based Assays
[0313] Apoptosis Induction.
[0314] Increasing concentrations of compound (Compound 2 and/or
MDV3100: 30 .mu.M) were spotted via an acoustic dispenser (EDC
ATS-100) into an empty 384-well plate in a 10-point serial dilution
fashion (3-fold dilution) in duplicate within the plate. Cells
(LNCaP, PC3 or VCAP) were then directly seeded at desired densities
to the compound-spotted 384-well plates. Cells were cultured for 48
hours at 37.degree. C./5% CO.sub.2 and were assessed via Caspase
3/7-Glo (Promega) and read for luminescence. Results are shown in
FIGS. 3B, C and D for LNCAP, and in FIG. 3E for VCAP, wherein
Compound 2 and MDV3100 combination treatment synergistically
induces apoptosis.
6.3 In Vivo Assays
[0315] ETS-Positive Prostate Cancer Xenograft Model.
[0316] Results are shown in FIGS. 1 and 2.
[0317] LNCap-HR Tumor Model.
[0318] A xenograft study was conducted with castration resistant
LNCaP (LNCaP-HR) tumor-bearing mice. Castration resistant LNCaP-HR
tumors were developed by several cycles of serial transplantation
and in vivo passaging of parental LNCaP tumor cells in castrated
SCID (severe combined immunodeficiency) mice. For xenograft
studies, tumor-bearing animals were generated by injecting
precisely determined numbers of cells or precise size of tumor
fragments subcutaneously in the flank region above the right hind
leg into castrated SCID mice. Following inoculation of animals, the
tumors were allowed to grow to a certain size prior to
randomization. The mice bearing LNCaP-HR xenograft tumors ranging
between 200 and 600 mm.sup.3 were pooled together and randomized
into various treatment groups. A typical efficacy study design
involved administering one or more compounds at various dose levels
to tumor-bearing mice. Additionally, reference chemotherapeutic
agents (positive control) and negative controls were similarly
administered and maintained. Routes of administration can include
intraperitoneal (IP) or oral (PO). Tumor measurements and body
weights were taken over the course of the study and morbidity and
mortality were recorded. Necropsy, histopathology, western blots,
MesoScale, immunohistochemistry and PCR can also be performed to
enhance understanding of disease and drug action. For a typical
xenograft study, SCID mice bearing LNCaP-HR tumors were randomized
and dosed with compounds ranging from, for example, 100 mg/kg to
0.1 mg/kg with different dose scheduling, including, but not
limited to, qd, q2d, q3d, q5d, q7d and bid. In certain studies a
combination of two or more agents were dosed simultaneously. The
compounds were formulated in various types of formulation. Some of
the formulations included CMC-Tween (0.5% CMC/0.25% Tween), NPS
(n-methylpyrrolidone, PEG, Saline), DMSO-CMC-Tween (1% CMC, 0.1%
Tween 80 and 5% dimethyl sulfoxide in water) and were delivered
orally or intraperitonially. The mice were dosed for 2-4 weeks.
Tumors were measured twice a week using calipers and tumor volumes
were calculated using the formula of W.sup.2.times.L/2. Statistical
analysis was performed using a one-way analysis of variance (ANOVA)
followed by Dunnett's post-hoc comparison with the vehicle-treated
control group.
[0319] The xenograft study was conducted with castration resistant
LNCaP-HR tumor-bearing mice. Castrated male SCID mice were
inoculated subcutaneously with LNCaP-HR cells in the flank region
above the right hind leg. Following inoculation of animals, the
tumors were allowed to grow to about 325 mm.sup.3 prior to
randomization. On Day 26 following tumor cell inoculation, the mice
bearing LNCaP-HR tumors ranging between 98 and 530 mm.sup.3 were
pooled together and randomized into various treatment groups.
Compound 2 was formulated in 0.5% CMC and 0.25% Tween 80 in water
(as a suspension). The animals were orally administered vehicle
(CMC-Tween) or Compound 2 once daily (QD) for up to 15 days. Doses
of Compound 2 ranged between 1 and 5 mg/kg. The positive control
MDV-3100 (50 mg/kg, Q4D) was administered via oral route. MDV-3100
was formulated in 1% CMC, 0.1% Tween 80 and 5% dimethyl sulfoxide
(DMSO) in water (as a suspension). Tumors were measured twice a
week using calipers and tumor volumes were calculated using the
formula of W.sup.2.times.L/2. Statistical analysis was performed
using a one-way analysis of variance (ANOVA) followed by Dunnett's
post-hoc comparison with the vehicle-treated control group. Results
are shown in FIG. 4.
6.4 Compound Formulations
[0320] Illustrative formulations of Compound 1 useful in the
methods provided herein are set forth in Tables 1-4, below.
TABLE-US-00002 TABLE 1 Amounts Ingredients mg % w/w Compound 1 20.0
15.38 Lactose monohydrate, NF (Fast Flo 316) 63.98 49.22
Microcrystalline cellulose, NF (Avicel pH 102) 40.30 31.00
Croscarmellose sodium, NF (Ac-Di-Sol) 3.90 3.00 Stearic acid, NF
0.52 0.40 Magnesium Stearate, NF 1.30 1.00 Total 130.0 100 Opadry
yellow 03K12429 5.2 4.0
TABLE-US-00003 TABLE 2 Amounts Ingredients mg % w/w Compound 1 5.0
3.80 Lactose monohydrate, NF (Fast Flo 316) 78.98 60.70
Microcrystalline cellulose, NF (Avicel pH 102) 40.30 31.00
Croscarmellose sodium, NF (Ac-Di-Sol) 3.90 3.00 Stearic acid, NF
0.52 0.40 Magnesium Stearate, NF 1.30 1.00 Total 130.0 100 Opadry
II pink 85F94211 5.2 4% weight gain
TABLE-US-00004 TABLE 3 Amounts Ingredients mg % w/w Compound 1 15.0
20.0 30.0 15.38 Lactose monohydrate, NF 48.37 64.50 96.75 49.62
(Fast Flo 316) Microcrystalline cellulose, NF 30.23 40.30 60.45
31.00 (Avicel pH 112) Croscarmellose sodium, NF 2.925 3.90 5.85
3.00 (Ac-Di-Sol) Magnesium Stearate, NF 0.975 1.30 1.95 1.00 Total
97.50 130.0 195.00 100 Opadry yellow 03K12429 3.9 4.0 Opadry II
Pink 85F94211 5.2 4.0 Opadry Pink 03K140004 7.8 4.0
TABLE-US-00005 TABLE 4 Amounts Ingredients mg % w/w Compound 1
45.00 15.38 Lactose monohydrate, NF (Fast Flo 316) 143.955 49.22
Microcrystalline cellulose, NF (Avicel pH 102) 90.675 31.00
Croscarmellose sodium, NF (Ac-Di-Sol) 8.775 3.00 Stearic acid, NF
1.170 0.40 Magnesium Stearate, NF 2.925 1.00 Total 292.50 100
Opadry pink 03K140004 11.70 4.0
[0321] Illustrative formulations of Compound 2 useful in the
methods provided herein are set forth in Table 5, below.
TABLE-US-00006 TABLE 5 Exemplary Tablet Formulations % w/w (mg)
Batch # Ingredients 1 2 3 4 Compound 2 (active ingredient) 10 10 10
10 Mannitol (Mannogem EZ) qs qs qs qs Microcrystalline Cellulose 25
25 25 25 (PH 112) Sodium Starch Glycolate 3 3 3 3 Silicon dioxide 1
1 1 1 Stearic acid 0.5 0.5 0.5 0.5 Disodium EDTA 0.5 0.5 BHT 0.4
0.4 Magnesium Stearate 0.65 0.65 0.65 0.65 Total 100 100 100 100
Color Yellow Yellow Yellow Yellow
[0322] A number of references have been cited, the disclosures of
which are incorporated herein by reference in their entirety. The
embodiments disclosed herein are not to be limited in scope by the
specific embodiments disclosed in the examples which are intended
as illustrations of a few aspects of the disclosed embodiments and
any embodiments that are functionally equivalent are encompassed by
the present disclosure. Indeed, various modifications of the
embodiments disclosed herein are in addition to those shown and
described herein will become apparent to those skilled in the art
and are intended to fall within the scope of the appended
claims.
* * * * *